ACTG DACS 325: Screening and Enrollment by Sex in HIV Clinical Trials in the United States
While women represent about one-quarter of adults living with HIV in the United States and over half of people living with HIV worldwide, many HIV clinical trials enroll fewer than 25% women. ACTG DACS 325 sought to assess how people living with HIV are recruited into the network’s clinical trials and whether ACTG enrolled proportionally lower percentages of women than men from the United States (and if so, why).
This analysis included all ACTG trials recruiting people living with HIV in the United States from 2003 (when the screening database started) through 2013. Researchers were not able to investigate gender identity, as it was not added to the ACTG screening questions until 2017. Data from 31 trials recruiting at 99 clinical research sites across the United States resulted in information on almost 11,000 participants. About one fifth (19%) of those screened were women living with HIV. Among those assessed, 28% did not enroll, which was only slightly higher than the 27% no enroll rate among men. These results did not differ when considering race, ethnicity, or age. The most common reasons for people not enrolling were not meeting trial requirements or persons opting-out and these reasons did not differ by sex. Pregnancy, breastfeeding, and trial contraceptive requirements were rarely reported as reasons to not enroll, though researchers speculate that women for whom these requirements applied may have been excluded (or excluded themselves) from trial consideration prior to screening.
Because the data around some of the factors relevant to participant recruitment (for example, childcare access, transportation, or participant reimbursement) were not available in the database, researchers were not able to address sex differences in the role of these factors in recruitment. Since there was no evidence for a significantly higher trial screen-out for women than men in this analysis, investigators concluded that approaching more women to screen may increase female representation in ACTG trials. This important analysis indicates that a strategy to expand eligibility and approach women prior to screening to assess barriers will help us in the important goal of increasing enrollment of women in all HIV clinical trials.
Smeaton, L.M., Kacanek, D., Mykhalchenko, K., Coughlin, K., Klingman, K.L., Koletar, S.L., Barr, E., Collier, A.C. Screening and Enrollment by Sex in HIV Clinical Trials in the United States. Clin Infect Dis. 2019 Sep 29;. doi: 10.1093/cid/ciz959. [Epub ahead of print] PubMed PMID: 31563942.
ACTG 5366: The Role of Women in HIV Cure-Related Research
Led by Dr. Eileen Scully of John Hopkins University and Dr. Rajesh Gandhi of Massachusetts General Hospital, A5366 is the first HIV cure-related clinical trial conducted entirely in women living with HIV. A5366 was presented at CROI 2020 and showed that women could both be recruited and retained in HIV cure research. Watch the full themed discussion here.
Of the 31 participants enrolled in the ACTG 5366, 29 agreed to undergo surveys and interviews to elicit their perspectives on the study (10 white; 18 Black/African American, 1 Native American). Almost all respondents reported positive experiences participating in A5366. The study also identified societal and personal motivators for participation, including the hope that HIV would be completely eliminated from the body, that they would never have to think of the virus again, and that they would not experience stigma for having HIV. Reimbursements to defray costs of study participation were reported by one-third of participants to aid in participation.
This paper showed that it is possible to embed participant-centered outcomes evaluations in ACTG studies. Moreover, these findings highlight the value of assessing psychosocial factors in participating in HIV cure-related research. The findings show us that people living with HIV join clinical trials for many different reasons and help us appreciate the lived experiences of participants. Greater attention should be paid to motivators that can help women overcome barriers of trial participation during the planning phase of clinical trials. Importantly, this study could help in the design and implementation of future HIV cure-related research efforts for women.
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
Brief Report: Sex Differences in Outcomes for Individuals Requiring Third-Line Antiretroviral Therapy (A5288)
In resource-limited settings, there are fewer regimens available to people living with HIV compared to individuals in resource-rich countries. Moreover, the options for people experiencing virological failure on protease inhibitor regimens are very limited. This paper describes the differences in the experiences of men and women who were referred for third-line therapy in ACTG sites in low- and middle-income countries.
More women entered study A5288 with a resistance pattern suggesting that they could still be suppressed on their current PI-based regimen and were therefore kept on that regimen, with changes in the NRTI backbone as needed. At the end of the study, fewer women than men achieved virological suppression. Women with virological failure more commonly had no new resistance mutations, suggesting incomplete adherence. Women were more likely to have symptoms that they graded as “severe,” and this group was less likely to achieve virological suppression.
Based on findings from other ACTG and non-ACTG studies that women have higher protease inhibitor plasma concentrations than men at the same dose, the authors hypothesize that increased drug levels lead to decreased tolerability of the PI regimens. Although ART regimens are given at a single dose for men and women, the clinical trials that led to the approval of most antiretrovirals often did not have adequate representation of women. Interventions designed to address or mitigate symptoms of ART in women may lead to improved virological success.
The main findings of A5288 were published earlier this year in Lancet HIV.
Godfrey, C., Hughes, M. D., Ritz, J., Coelho, L., Gross, R., Salata, R., Mngqibisa, R., Wallis, C. L., Mumbi, M. E., Matoga, M., Poongulali, S., Van Schalkwyk, M., Hogg, E., Fletcher, C. V., Grinsztejn, B., & Collier, A. C. (2020). Brief Report: Sex Differences in Outcomes for Individuals Presenting for Third-Line Antiretroviral Therapy. Journal of Acquired Immune Deficiency Syndromes (1999), 84(2), 203–207. https://doi.org/10.1097/QAI.0000000000002324
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Cure Research: INTACT PROVIRAL DNA LEVELS DECLINE IN PEOPLE WITH HIV ON ANTIRETROVIRAL THERAPY (ART) (ACTG 5321; Oral Abstract Session 0-06: Targeting the Persistent HIV Reservoir) Rajesh T. Gandhi, et al. Topic: HIV Cure, the Reservoir, and Persistence. Watch the full CROI 2020 presentation HERE.
Read the full manuscript here!
Gandhi, R. T., Cyktor, J. C., Bosch, R. J., Mar, H., Laird, G. M., Martin, A., Collier, A. C., Riddler, S. A., Macatangay, B. J., Rinaldo, C. R., Eron, J. J., Siliciano, J. D., McMahon, D. K., Mellors, J. W., & ACTG A5321 team (2020). Selective Decay of Intact HIV-1 Proviral DNA on Antiretroviral Therapy. The Journal of infectious diseases, jiaa532. Advance online publication. https://doi.org/10.1093/infdis/jiaa532
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A5288: Diverse Drug Resistance Profiles among People Experiencing Virologic Failure on Second-line ART in Resource Limited Settings
A5288 assessed third-line antiretroviral treatment (ART) in individuals who were failing second-line ART. This publication aimed to define resistance profiles among individuals failing second-line ART in low- and middle-income countries (LMIC), as this information is vital to optimize individual patient management and develop treatment guidelines for this group. Of the 653 individuals screened for A5288, more than three-quarters (78%) had resistance to one or more drugs. One-fifth (20%) of participants showed resistance to at least one drug in a drug class, 32% showed resistance to at least one drug in two drug classes, and 26% showed resistance to at least one drug in all three commonly available drug classes. Susceptibility to at least one second-line regimen available in LMICs was preserved in 59% of individuals, as was susceptibility to etravirine (78%) and darunavir/r (97%). Susceptibility to a second-line regimen was significantly higher among women, younger individuals, those with higher nadir CD4+T-cell count, and those who had received LPV/r, and was lower among prior nevirapine recipients.
These results underscore the need for ready access to resistance testing and newer antiretrovirals for optimal management of third-line ART in LMIC.
Wallis C., Hughes M., Ritz J., Viana R., Jesus C., Saravanan S., Van Schalkwyk M., Mngqibisa R., Salata R., Mugyenyi P., Hogg E., Hovind L., Wieclaw L., Gross R., Godfrey C., Collier A., Grinsztejn B., Mellors J. Diverse HIV-1 Drug Resistance Profiles at Screening for ACTG A5288: A Study of People Experiencing Virologic Failure on Second-line ART in Resource Limited Settings. Clin Infect Dis. 2019 Nov 14;. doi: 10.1093/cid/ciz1116. [Epub ahead of print] PubMedID: 31724034.
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A5263: Optimizing Treatment for Kaposi’s Sarcoma In Resource Limited Settings
Dr. Susan E. Krown and colleagues published “Treatment of Advanced AIDS-associated Kaposi Sarcoma in Resource-limited Settings: a Three-arm, Open-label, Randomized, Non-inferiority trial” from the A5263 trial in The Lancet on April 11, 2020. A5263 studied optimal treatment strategies for advanced-stage disease in resource-limited settings. Participants with HIV and advanced-stage AIDS-associated Kaposi Sarcoma (KS) were recruited from 11 ACTG sites in Brazil, Kenya, Malawi, South Africa, Uganda, and Zimbabwe. Eligible participants were randomly assigned (1:1:1) to receive either intravenous bleomycin and vincristine or oral etoposide (the investigational arms), or intravenous paclitaxel (the control arm), together with standard EFV-based ART.
Three hundred thirty-four participants were enrolled between October 1, 2013 and March 8, 2018, when the study was closed early due to inferiority of the bleomycin and vincristine plus ART arm. The etoposide plus ART arm had previously closed due to inferiority in March 2016. Week 48 progression-free survival rates were higher in the paclitaxel plus ART arm than in both investigational arms. Rates of adverse effects were equal across arms. Non-inferiority of either investigational intervention for advanced KS in LMICs was not demonstrated. Paclitaxel plus ART should continue to be used in treating advanced AIDS-associated KS in resource-limited settings.
Krown S., Moser C., Campbell T., MacPhail A., Matining R., Godfrey C., Caruso S., Hosseinipour M., Samaneka W., Nyirenda M., Busakhala N., Okuku F., Kosgei J., Hoagland B., Mwelase N., Oliver V., Burger H., Mngqibisa R., Nokta M., Borok-Williams M. Treatment of Advanced AIDS-associated Kaposi Sarcoma in Resource-Limited Settings: A Three-Arm, Open-Label, Randomised, Non-Inferiority Trial in Five sub-Saharan African Countries and Brazil (ACTG A5263/AMC066). Lancet Vol. 395. Iss 10231. 2020 Apr 11;. doi: 10.1016/S0140-6736(19)33222-2. Epub 2020 Mar. PubMedID: 32145827
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HIV AND CARDIOVASCULAR RISK
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Does Overall Cardiovascular Risk Predict Future Cognitive Function in People Living with HIV?
Memory problems, difficulty concentrating, and inability to multi-task, among other cognitive issues, are common complaints of people living and aging with HIV. Although our understanding of the causes of cognitive dysfunction in people living with HIV is limited, there are a number of conditions that have been shown to increase the risk of cognitive impairment. Cardiovascular risk factors, including a history of heart disease, diabetes mellitus, and high cholesterol, seem to play an important role in the development of cognitive issues in people with and without HIV. Therefore, this study, which was embedded in the A5322 study (Long-Term Follow-up of Older HIV-infected Adults in the ACTG: Addressing Issues of Aging, HIV Infection and Inflammation (HAILO)), sought to investigate whether having a combination of several cardiovascular risk factors might help predict impairments in cognitive function in the future.
The authors calculated a cardiovascular risk score for participants at the time they entered A5322 using the following data: age, sex, race/ethnicity, systolic blood pressure, total cholesterol, HDL cholesterol (the “good” cholesterol), use of blood pressure medications, current smoking, and a history of diabetes mellitus. Cognition was assessed every year in A5322 using a series of pen and paper tests that measure memory, speed of information processing, attention, and executive function. Among the 988 participants ≥40 years included in this study, a higher cardiovascular risk score at the first study visit could predict poorer cognitive function four years later at a follow-up visit. When sex differences were examined, the harmful effect of a higher cardiovascular risk score on future cognitive function was much more pronounced in women than in men.
These results suggest that cardiovascular risk factors are an important contributor to cognitive issues in all people living with HIV, but particularly in women. Estimating someone’s cardiovascular risk using a simple cardiovascular risk score (e.g., the Atherosclerotic Cardiovascular Disease risk score) may help to identify people, especially women, who are at risk for worse cognition over time. Further work is needed to examine whether lowering cardiovascular risk through addressing risk factors could reduce the risk of future cognitive impairment.
Chow, F. C., Lyass, A., Mahoney, T. F., Massaro, J. M., Triant, V. A., Wu, K., Berzins, B., Robertson, K., Ellis, R. J., Tassiopoulos, K., Taiwo, B., D'Agostino, R. B., Sr, & ACTG A5322 Study Team (2020). Baseline 10-year cardiovascular risk scores predict cognitive function in older persons, and particularly women, living with HIV infection. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America, ciz1214. Advance online publication. https://doi.org/10.1093/cid/ciz1214
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 (MIs or heart attacks). Because traditional risk scores for predicting myocardial infarction do not take these HIV-specific drivers into account, prediction tools can be inaccurate in people living with HIV. 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 investigation did not use specimens from a single trial, but innovatively utilized samples stored in the ACTG specimen repository, identifying individuals across ACTG studies who had experienced an MI while enrolled in a study. 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.
The study found that 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. 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 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 in people with HIV or if this biomarker can be affected by anti-inflammatory medications.
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
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, the study also assesses non-CVD comorbidities – which 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. Moreover, congratulations to ACTG REPRIEVE, for receiving a ViiV Global HIV and COVID-19 Emergency Response Fund grant! ViiV included REPRIEVE as one of 109 grantees out of over 400 grant applications.
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Dapivirine Ring: The Microbicide Trials Network (MTN) announced that the European Medicines Agency (EMA) adopted a positive scientific opinion on the monthly dapivirine vaginal ring’s use in low- and middle-income countries. The International Partnership for Microbicides, which developed the ring, now plans to submit applications to national medical regulatory authorities in east and southern Africa, in collaboration with the WHO, and the FDA later this year. Congratulations to the study team on their progress on this important new HIV prevention method for women!
Injectable Cabotegravir: In July and November, HPTN released data on studies 083 and 084, respectively. These breakthrough studies assessed a long-acting injectable drug to prevent HIV acquisition in cisgender men, cisgender women, and transgender women and have the potential to significantly alter the HIV treatment landscape. Congratulations to our colleagues at HPTN!
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WHAT WORLD AIDS DAY MEANS TO US
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Members of the ACTG Network shared their thoughts about the importance of World AIDS Day and what it means to them. Below are some of the responses we received. To see more, follow us on Twitter and Instagram (@ACTGNetwork) and like our page on Facebook (www.facebook.com/AIDSClinicalTrialsGroup/)! Thank you everyone who participated!
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“World AIDS Day is the time to remember those we have lost, those who remain healthy in our care, and hoping the future brings an end to the HIV epidemic.”
Dr. Mina Hosseinipour – University of North Carolina
“World AIDS Day, is a time to remember and honor the people that this virus took from us too early, and what and who they could have been. It’s also a time to be thankful for the advances we have since then, that make our lives easier. It is also a day for us to stand up and say we will help protect the future of others.”
Timmy Brehm – Johns Hopkins University, CAB Chair
“Gone are the days when a diagnosis of a positive HIV status was regarded as doom and gloom. Research has enabled great ARV implementations and roll out to communities who need it most at no cost. A very comforting thought especially now that interventions are also benefitting children from birth.”
Marie E. Martins – FAMCRU, CAB Member and Adherence Monitor
“For me World AIDS Day is important to acknowledge and appreciate the efforts and contribution of various government and non-government, national and international organisations, scientists, communities and people living with HIV who are tirelessly working to find a cure, vaccine and various treatment strategies for HIV/AIDS.”
Sushma Dadar – BJMC CRS, Study Counsellor
“World AIDS Day COVID-19 2020, for me, is a reminder of how far we’ve come since HIV/AIDS was first diagnosed and how far we still have to go to end our new reality. So, instead of feeling bad, realize that we are all in this together so we have solidarity. We also have shared responsibility; when I was diagnosed with HIV, I didn’t want to give it to anyone else and I know (hope?) that is how people with COVID-19 feel. For those with the virus, there is a responsibility to be safe (just like with HIV) and for those who aren’t, you have a responsibility to not judge. Viruses are not spread to bad people for doing something wrong. Viruses don’t know their host (the person with the virus). In this we are all EQUAL. Now’s the time to heal mentally, spiritually and physically. A holistic approach is needed to mend hearts, souls, and our nation. Our healing won’t happen overnight, it will take time and perseverance. I have faith that together, with the grace of GOD, this too shall pass.”
Gail Graham – Johns Hopkins University, CAB Representative
“World AIDS Day to me means a time to stop and reflect on the countless friends and lovers we have lost to this horrible disease and renew our fight to continue to work towards a CURE. This photo is one of the panels our ACTU CAB is sponsoring for WAD in the virtual quilt display featuring an incredibly significant leader our community lost.”
David Andrist – Ohio State University, Outreach/Education Coordinator
“It is a day of celebrating those living with HIV/AIDS, and a day of remembering and honouring the lives lost to HIV/AIDS. While we celebrate the progress, we reflect on the work that still needs to be done.”
Zani de Wit – University of Cape Town Lung Institute, Community Engagement Officer
“I would like to reflect back on all those we have lost along this journey in our effort to find answers and help for those infected and affected by HIV. I would like to remember my friend, Robert Zackin, who had a zest for life and a wicked sense of humor. I miss our conversations and visits. On this day, I remember his spirit and contributions and know that we will push on till we someday finally find a cure.”
Dr. Carl Fichtenbaum – University of Cincinnati |
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INVESTIGATOR SPOTLIGHT
Vidya Mave, MD, MPH
Dr. Vidya Mave is Leader and Director of Byramjee-Jeejeebhoy Government Medical College-Johns Hopkins University (BJGMC-JHU) CRS based in Pune, India, where she oversees all clinical research activities for the CRS. This includes phase 1, 2, and 3 clinical trials of therapeutic drug interventions for HIV and co-morbid infections, including TB in adults (including pregnant women), adolescents and children. She is an Assistant Professor in the Division of Infectious Diseases at Johns Hopkins University School of Medicine.
Dr. Mave has nearly 18 years of experience in clinical practice, education, and research in infectious diseases. She serves as a member of the ACTG TB transformative science group and cross-network TB vaccine working group. She is the current co-Chair of A5384, a phase 2 trial in planning phase aiming to optimize regimens for TB meningitis, a disease with high morbidity and mortality. She is also vice-Chair of A5397, a planning phase trial, which proposes to assess the ID 93 TB vaccine as a potential therapeutic vaccine. She is lead investigator for a phase 2/3 clinical trial on the efficacy and safety of VPM 1002, a recombinant BCG vaccine, to prevent TB recurrence, and she directs a large observational cohort in Pune investigating the epidemiology of HIV in India. She served as Chair of the Common Protocol for the Regional Prospective Observational Research in Tuberculosis (RePORT) India Consortium, a collaboration among six Indian and U.S. research/teaching institutions that is part of an international effort to identify and validate biomarkers that predict TB treatment outcomes and progression from latent infection to active disease.
Dr. Mave participated in two World Health Organization workshops that formulated guidelines on HIV vertical transmission management and TB clinical trial designs, respectively. In addition, Dr. Mave has mentored 20 pre- and post-doctoral trainees from India and Johns Hopkins, as well as trainees participating in the BJGMC-JHU HIV-TB Fogarty Research Training Program. She is an author of more than 100 peer-reviewed publications.
Dr. Mave received an M.D. in medicine from Karnatak University, Dharwad, India, and an M.P.H. from Tulane University. She completed her internal medicine training at St. Barnabas Hospital in New York, followed by a post-doctoral fellowship in infectious diseases at Tulane University and Long Island Jewish Medical Center.
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CAB MEMBER SPOTLIGHT
Salim Bakari, Eldoret, Kenya
Salim Bakari is a CSS member, peer counselor, and advocate who strives to learn new scientific information in order to impact the youth affected by and infected with TB and HIV. He is particularly interested in clinical research, human research, sexual reproductive health, advocacy, and governance.
Salim currently represents the community views and opinions as a member of the TB TSG. His responsibilities include contributing to the scientific agenda and providing input as a CSS member to protocol drafts that are presented to CAB members for input. “I have a duty to enlighten my community about the basic scientific approach and informing them about the importance of research studies,” he says.
“Being in [the] ACTG as a community member means a lot. It’s a platform where science meets the community and the community meets science. All these are broken down in several subcommittees where we, the community, are able to learn and share our different ideologies. It also means being able to represent the voice of those who feel they are not being heard and ensuring their needs when it comes to clinical research are taken seriously and their rights are respected.
“For me, World AIDS Day means commemorating the journey and strides that we have taken as a community to reach where we are today. It has been tough but it’s worth it, and the future is promising. It is celebrating the lives of our departed heroes who died due to AIDS or died fighting for a better community, which is free and safe for all the HIV community. With COVID-19 around and looking at the year 2020, I conquer and stand with the theme ‘Global Solidarity, Shared Responsibility.’ This is what can save us all.”
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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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