ACTG Newsletter - November 2020

LANDMARK TRIAL DEMONSTRATES EFFECTIVENSS OF SHORTENED TB TREATMENT
The ACTG is pleased to share the primary results of Study 31/A5349, which were presented at the 51st virtual Union World Conference on Lung Health on October 21st, 2020. This important study showed that the four-month regimen of rifapentine, isoniazid, pyrazinamide, and moxifloxacin (RPT-MOX) was non-inferior to the currently recommended six-month regimen of rifampicin, isoniazid, ethambutol, and pyrazinamide for the treatment of drug-susceptible pulmonary TB. RPT-MOX was also safe and well-tolerated by patients. A second four-month regimen of rifapentine, isoniazid, pyrazinamide, and ethambutol failed to meet the non-inferiority margin.

To put this study in historical context, the last time pulmonary TB treatment was successfully shortened for drug-susceptible TB was 48 years ago, when the British Medical Research Council (MRC) published results showing a six-month regimen was as effective as the standard 18-month regimen at that time. Despite many trial attempts to shorten TB therapy since, the standard treatment regimen for drug-susceptible pulmonary TB has remained at six months.

Thirteen countries contributed to Study 31/A5349, a phase 3, open-label, randomized controlled clinical trial, at 34 clinical sites. Approximately 2,500 people aged 12 years and older participated in the study, including 214 people with HIV infection. The study was led by the CDC Tuberculosis Trials Consortium (TBTC) in collaboration with the ACTG. ACTG sites enrolled two-thirds of participants and TBTC sites enrolled one-third.

Participants with HIV infection were enrolled in a staged fashion to allow for drug-drug interaction studies between rifapentine and efavirenz, which is why the number was relatively small. Reassuringly though, the participants did just as well as those without HIV, and the RPT-MOX regimen was also non-inferior and safe in these participants.

“Shortening treatment for TB has been front and center in the TB TSG scientific agenda for decades, and this new regimen that reduces treatment by two months will facilitate significant progress in global tuberculosis control,” said Dr. Susan Swindells of the University of Nebraska Medical Center and a co-chair of the study.

“This trial demonstrates the value of collaborative efforts between the ACTG and other networks,” added Dr. Richard Chaisson of Johns Hopkins University, another co-chair of the trial.

Shortening TB treatment to four months instead of six represents a major advancement in the management of this age-old infectious disease. Congratulations to the study team and participating sites for this astounding achievement!

A5360 RESULTS TO BE PRESENTED AT AASLD
The ACTG is thrilled to announce that the results of A5360 (Monitoring SOF-VEL in Treatment Naive, HCV Participants with Active Infection) will be presented at the Liver Meeting (AASLD) on November 16. A5360 evaluated the safety and efficacy of a minimal monitoring (MINMON) approach to hepatitis C therapy in people who had not received prior treatment and had no evidence of decompensated cirrhosis. In this study, the MINMON strategy comprised of four elements: no genotyping prior to treatment, all tablets dispensed at entry, no scheduled on-treatment clinic visits or labs, and two remote contacts at weeks four (an adherence assessment) and 22 (scheduling a sustained virologic response – SVR – visit). All participants received a single-tablet, fixed-dose regimen of sofosbuvir/velpatasvir for 12 weeks.

A5360 demonstrated that in a diverse global patient population recruited across four continents, a MINMON approach to HCV treatment delivery was safe and achieved SVR comparable to current standards. Wider adoption of the MINMON strategy, coupled with innovative case-finding strategies, may facilitate the elimination of hepatitis C while minimizing in-person appointments and resource use.

In order to achieve the WHO’s global hepatitis C elimination agenda by 2030, it is estimated that 80 percent of the approximately 71 million people with chronic infection will need to be treated. To accomplish this, treatment delivery and associated laboratory monitoring need to be simplified without compromising efficacy or safety. The COVID-19 pandemic has hampered progress of public health programs including the viral hepatitis program, further highlighting the need for simple and safe models of healthcare delivery that minimize face-to-face patient-provider contact without compromising efficacy.

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 living with HIV, similar to what is observed in the general population. 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 included in this study, all of whom were 40 years of age and older, we found that a higher cardiovascular risk score at the first A5322 study visit could predict poorer cognitive function four years later at a follow-up visit. Because studies have shown that the risk factors for cognitive impairment in women may be different than in men, the authors also analyzed participants separately by sex. When the group was split into women and men, we observed that 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. We need to learn more about whether lowering cardiovascular risk (e.g., taking blood pressure medications, staying physically active, quitting smoking) can actually reduce the risk of cognitive impairment and slow cognitive decline in people living with HIV. Given the differences in how cardiovascular risk may affect the cognition of women and men living with HIV, it is especially important for women living with HIV to be included in future studies investigating ways to lower cardiovascular risk and improve brain health.

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

A5260s: Working to Understand the Impact of Antiretroviral Therapy on Adipose Tissue Function in People Living with HIV
Disturbances in adipose tissue (AT), also known by the general public as “fat,” in people living with HIV include lipodystrophy (fat loss or gain) and obesity. AT quality, in addition to quantity, are closely associated with the development of cardiovascular disease. AT quality can be indirectly assessed by quantifying AT density (in Hounsfield units, HU) on computed tomography (CT); decreases in AT density suggest disrupted adipocyte function. Limited studies have explored the relationship between AT quality and antiretroviral therapy (ART). A5260s is a prospective substudy of a phase 3 randomized clinical trial (A5257) that investigated NNRTI-sparing regimens for the initial treatment of HIV. Investigators in A5260s sought to describe the effects of ART initiation on visceral AT (VAT) and subcutaneous AT (SAT) density, and to determine relationships between AT density and circulating inflammatory biomarkers on cardiovascular disease.

The participants of A5260s were initiated on ART in the context of A5257 for 96 weeks. Both SAT and VAT density decreased after 96 weeks of treatment with women having larger decreases. Less dense AT also correlated with greater disruptions of lipid and glucose metabolism. For instance, decreases in VAT and SAT density correlated with decreases in adiponectin levels and increases in leptin levels, both of which have been associated with greater cardiometabolic risk. These findings suggest that ART leads to changes in AT density (independent of AT quantity), which may have deleterious effects on cardiovascular risk.

Debroy, P., Lake, JE., Moser, C., Olefsky, M., Erlandson, KM., Scherzinger, A., Stein, JH., Currier, JS., Brown, TT., and McComsey, GC. ART initiation is associated with decreased visceral and subcutaneous adipose tissue density in people living with HIV. Clinical Infectious Diseases 2020 Feb. doi 10.1093/cid/ciaa196

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. There is usually a single “first-line” regimen (mainly dolutegravir-based with efavirenz as an alternative) and a “second-line” regimen (with the protease inhibitors lopinavir/ritonavir or atazanavir/ritonavir, as backbones). 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 have been suppressed on their current PI-based regimen. Consistent with guidelines, these women were therefore kept on their protease inhibitor-based 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” or that interfered with their daily living, although laboratory values were not significantly more abnormal in women than men. The group of participants that reported severe symptoms was unlikely to achieve virological suppression.

Based on findings from other ACTG and non-ACTG studies that women have higher protease inhibitor plasma concentrations then men at the same dose, the authors hypothesize that increased drug levels lead to decreased tolerability of the PI regimens. The decrease in tolerability will result in lapses in adherence and ultimate virological failure. 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 improve and mitigate symptoms of ART in women may lead to improved virological success. Moreover, counseling of women should include a systematic assessment of adherence barriers, including tolerability concerns.

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

ACTG and COVID-19

Using a combination of demographic and clinical data gathered from COVID-19 patient care early in the coronavirus pandemic (“the first wave”), ACTG researcher Amita Gupta, M.D. (BWI CTU co-PI, Professor of Medicine and International Health at the Johns Hopkins University), Brian Garibaldi (first author and Johns Hopkins physician who was on Trump’s COVID care team), and their Hopkins colleagues, published a study in Annals of Internal Medicine September 2020 entitled “Patient Trajectories Among Persons Hospitalized for COVID-19.” They developed a prediction model that can help other hospitals design care paradigms for COVID-19 patients. This study analyzed data from five Johns Hopkins-affiliated hospitals in the Maryland and Washington DC region that were involved in the care of COVID-19 patients age 18 or older — 336 Black, 264 white, 135 Hispanic, 48 Asian, 2 Native American and 42 multiracial — who tested positive for the coronavirus and had symptoms of COVID-19. The study’s data comes from a registry of all patients treated for COVID-19 at hospitals in the Johns Hopkins system. Known as “JH-CROWN,” the registry offers demographics, diagnoses, procedures, social histories, and other data points relevant to caring for COVID-19 patients.

The prediction model uses a set of risk factors known to be associated with COVID-19 to forecast how likely a patient’s disease is to worsen while being treated in a hospital and at what point in their care that worsening might happen. Among the risk factors researchers considered were a patient’s age, body mass index (BMI), lung health, and chronic disease, as well as vital signs and the severity of a patient’s COVID-19 symptoms at the time of admission. The model, called the “COVID Inpatient Risk Calculator (CIRC),” is available online.

“We identified a few readily measurable demographic and clinical factors that, when assessed on admission to the hospital, can predict if someone has a 5 percent or a 90 percent risk of developing severe disease or dying from COVID-19,” says Dr. Gupta. “This is incredibly useful information to have when communicating with patients and their families, as well as for informing resource allocation in the hospital.”

As an example, using the CIRC model, a 60-year-old white woman with a BMI of 28, no chronic disease and no fever who is hospitalized for COVID-19 has a 10 percent chance of her disease worsening by day two of her hospital stay. The longer she is in the hospital, the greater that chance becomes, increasing to 15 percent after four days and 16 percent after a week. Conversely, the researchers considered an 81-year-old Black woman admitted to the hospital with COVID-19. This hypothetical woman has a BMI of 35, diabetes, hypertension, and a fever. CIRC forecasts her probability of progressing to severe disease or even death by just the second day of her hospital stay at 89 percent. That percentage increases to higher than 95 percent by days four and seven. They are now refining and validating the risk calculator tool using other datasets in order to continue to help inform how clinicians caring for people with COVID-19 will triage them in the hospital.

Garibaldi, B. T., Fiksel, J., Muschelli, J., Robinson, M. L., Rouhizadeh, M., Perin, J., Schumock, G., Nagy, P., Gray, J. H., Malapati, H., Ghobadi-Krueger, M., Niessen, T. M., Kim, B. S., Hill, P. M., Ahmed, M. S., Dobkin, E. D., Blanding, R., Abele, J., Woods, B., Harkness, K., Thiemann, D. R., Bowring, M. G., Shah, A. B., Wang, MC., Bandeen-Roche, K., Rosen, A., Zeger, S. L.,Gupta, A. Patient Trajectories Among Persons Hospitalized for COVID-19: A Cohort Study. Annals of Internal Medicine 0;0 [Epub ahead of print 22 September 2020]. doi: https://doi.org/10.7326/M20-3905

ACTG TRIALS REOPENING

INVESTIGATOR SPOTLIGHT

Edgar Turner Overton, MD

Edgar Turner Overton, MD, is a Professor of Medicine in the Division of Infectious Diseases at the University of Alabama at Birmingham (UAB) School of Medicine. He serves as the Medical Director of the UAB 1917 HIV Clinic and as a Co-Director of the Clinical Core of the UAB Center for AIDS Research, working with like-minded scientists who are interested in developing translational research to prevent complications of HIV disease. His research interests focus on comorbidities in the setting of HIV, particularly in the current era when AIDS-defining illnesses have declined, but age-related diseases remain prevalent. He currently has an R01 from the National Institute of Diabetes and Digestive and Kidney Diseases evaluating the role of pitavastatin to prevent the progression of kidney function decline in the setting of HIV infection as a substudy of the REPRIEVE Trial (A5332). Dr. Overton also serves as co-PI with Dr. Paul Muntner on the UAB K12 Career Development Grant funded by National Heart, Lung, and Blood Institute (NHLBI) to expand the pool of researchers working on NHLBI-related issues among people with HIV. One of the key attractions for him to join the UAB ID faculty was the opportunity to collaborate with other investigators and to participate in the mentoring of young investigators to improve the health of people living with HIV in the South, where health disparities are highly prevalent.

Dr. Overton completed his Infectious Disease training at Washington University in St. Louis, Missouri (Go Cards!), where he had the good fortune to receive mentorship from Drs. Judy Aberg, Pablo Tebas, Vicky Frazier, Kevin Yarasheski, Jerry Medoff, and Bill Powderly. When Drs. Aberg, Tebas, and Powderly “abandoned him” for new challenges at other institutions, Dr. Overton partnered with Dr. David Clifford to lead the Washington University ACTG site, working closely with Michael Klebert, PhD, Lisa Kessels, Mike Royal, PharmD, Warren Seyfried and a group of collaborators to develop a strong foundation in HIV clinical research that has served him well. Working with Dr. Yarasheski and his research team, Dr. Overton gained an appreciation for metabolic complications of HIV and HIV treatments, preparing him for his future work.

In 2011, Dr.Overton accepted a position at UAB and has spent the last decade expanding their HIV clinical trials site. He currently serves as the Principal Investigator of the Alabama to Zambia (A-to-Z) Clinical Trials Unit with sites in both UAB (Alabama CRS 31788) and Zambia (Center for Infectious Diseases Research in Zambia (CIDRZ) Matero Reference Clinic CRS 30290). He currently serves as the Chair of the End Organ Disease/Inflammation Transformative Science Group (TSG) for the ACTG and in close collaboration with Dr. Netanya Utay, the TSG Vice-Chair. Dr. Overton has served on numerous protocols during his tenure in the ACTG, including as the protocol chair for A5220 (HBV Vaccine), A5350 (Visbiome ES), and A5332 (REPRIEVE). As the protocol chair for REPRIEVE, he has been very engaged in expanding the awareness of external investigators and sponsors to the potential of the ACTG as a network to perform high-quality studies.

In his spare time, Dr. Overton is a key member in the UAB efforts to tackle the COVID-19 pandemic that is having devastating effects in populations already affected by health disparities. He is the Clinic Director for the COVID Respiratory Clinic, where patients can be safely evaluated while still infectious. He is also leading local trials to for both treatment and prevention of COVID-19. While Dr. Overton works too much (per his 10 year-old daughter), he would rather be in the woods with his kids, walking their dogs Hugo and Penny, listening to some good music and escaping the current political climate.

CAB MEMBER SPOTLIGHT

NEWS TO SHARE?

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