ACTG Newsletter - December 2019

ANNOUNCEMENTS

New ACTG Website Launches!

We are thrilled to announce the new ACTG website is now live! Check it out here! We've overhauled the site to be more user friendly, accessible, and helpful to our audiences. The site features recent publication highlights, information on our committees and centers, community resources, and more! We hope you find the website useful and helpful.

ACTG Commemorates World AIDS Day
By Joe Eron

The impact of HIV on our world is difficult to estimate. There is no region of the world that is unaffected. While HIV has impacted superstars, governments, and continents, its most dramatic effect is on those who are most disadvantaged, including individuals who face stigma, shame, and poverty. If you speak long enough to almost anyone, you learn that they’ve had a family member or friend or colleague with HIV, many of whom have died. No one is “immune”. I have my “suburban housewife day” in HIV clinic and my (now) “great-grandmother day.”

World AIDS Day provides the ACTG and the rest of the world an opportunity to reflect, remember, and mourn, but also to hope, plan, and focus. Together we have made tremendous progress on many fronts, including better understanding of HIV pathogenesis and the human immune response to HIV, and remarkable advances in HIV treatment and prevention. Soon there will be 20 million people on antiretroviral therapy (ART) worldwide. Fifty years from now, when history books (if they still exist) write about the most important events of the early 21^st century, PEPFAR will be included – maybe even at the top of the list. Life expectancy for those who can access and navigate ART has been extended, approaching that of people who don’t have HIV. Treatment can be simple and it is safer than it has ever been. Prevention interventions, including interruption of perinatal transmission, male circumcision, and PrEP, have reduced new HIV infections in many areas.

However, many people no longer regard HIV as a critical issue. World AIDS Day is an opportunity to remind the world that there is still much work to be done.

If there are 20 million people on ART, that means there are 20 million who need to be and are not
In the U.S., the number of new HIV infections has not declined substantially in the last four years
Access to treatment and navigating healthcare systems is frequently difficult and syndemics of poverty, substance use, intimate partner violence, depression, tuberculosis, and hepatitis impede progress
The impact of HIV on the co-morbidities of aging is incompletely understood and we lack interventions to fully reverse immune dysfunction
There is no vaccine for HIV
There is no cure

The ACTG (our staff, community, investigators, and leaders) are committed to clinical research that addresses many of these remaining hurdles. We are dedicated to developing and making available novel interventions, including long-acting therapy and potentially broadly neutralizing HIV antibodies, for all people living with HIV around the world who need novel treatments, regardless of their resource level. We commit to the study of ART-free remission and (yes) even the HIV cure. We are a premier TB Network, developing therapy for this devastating infection in people with and without HIV. We accept the challenge of contributing to a functional cure for hepatitis B and are working to develop interventions for persistent immune dysfunction and teaming up with experts and funders to develop therapies for co-morbid conditions that impact people with HIV.

On World AIDS Day, we recognize that there is a lot to remember and much to be done. I know that all of us in the ACTG are committed to continuing to roll up our sleeves and working to end the HIV epidemic.

PHOENIx Generates Media Coverage
ACTG’s PHOENIx (Protecting Households On Exposure to Newly Diagnosed Index Multidrug-Resistant Tuberculosis Patients (A5300B/I2003B) study was the focus of media coverage about the 50^th World Union Conference on Lung Health in Hyberadad, India in November. PHOENIx is a Phase 3, open-label, multicenter trial to compare the efficacy and safety of 26 weeks of delamanid versus 26 weeks of isoniazid for preventing confirmed or probable active TB among high-risk household contacts of adults with multidrug-resistant tuberculosis (MDR-TB). This ACTG/IMPAACT cross-network collaboration expects to follow 5610 participants (~2158 index cases and 3452 HHCs) for 96 weeks. Coverage about this groundbreaking study appeared in Agence France Press, as well as Indian publications The Wire, The Hindu/Business Line, and The Indian Express, and Filipino publications The Philippine Star and Business Mirror. Please check it out!

PUBLICATIONS

This month’s newsletter highlights three important ACTG publications. Please check out the full list of ACTG publications on PubMed.

A5334s: Differences in Drug Interactions Between those with HCV, HIV, and HIV/HCV Coinfection
One form of treatment for Hepatitis C virus (HCV) is composed of ombitasvir, paritaprevir/ritonavir- plus dasabuvir (OBV/PTV/r + DSV), and weight-based ribavirin. Study A5334s, a pharmacokinetics sub-study to A5329 (which evaluated this interferon-free HCV treatment among people living with HIV), sought to understand if concentrations of raltegravir changed after this HCV treatment was initiated among people living with HIV and HCV.

Compared to raltegravir levels before initiating HCV therapy, raltegravir levels four weeks after co-administration of this HCV combination in people living with HIV and HCV were unexpectedly lower in the majority (73%) of participants, although confidence intervals were wide. These decreases in raltegravir exposures were not suspected to be clinically important, as there were no HIV virologic failures reported in this group. Nonetheless, study A5334s reminds us to study drug-drug interactions carefully in those living with HIV on HCV treatment.

Venuto CS, Cramer YS, Rosenkranz SL, Sulkowski MS, Wyles DL, Cohen DE, Alston-Smith BL, Morse GD. Raltegravir Pharmacokinetics Before and During Treatment with Ombitasvir, Paritaprevir/Ritonavir Plus Dasabuvir in Adults with HIV-1 and Hepatitis C Virus Co-Infection: AIDS Clinical Trials Group Sub-Study A5334s. British Journal of Clinical Pharmacology 2019 Oct 27. doi: 10.1111/bcp.14148. [Epub ahead of print]

NWCS 399: CT as Non-Invasive Assessment of Fat Quality
Fat quality or function contributes to risk for diseases such as heart disease, fatty liver disease, and diabetes, and may be as important as fat quantity when assessing the risk of poor health outcomes. In the past, fat quality could only be determined by performing fat biopsies and measuring fat cell size under the microscope. However, measuring fat cell density on a CT scan may also measure fat quality (lower density=poorer quality/more poorly functioning fat cells). NWCS 399 compared data from abdominal subcutaneous fat biopsy specimens, with fat density data from CT scans in the ACTG A5224s (a sub-study of A5202, which randomized adults living with HIV to abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) with open-label efavirenz (EFV) or atazanavir/ritonavir (ATV/r)).

Subcutaneous abdominal fat density was on the CT scans in Hounsfield Units (HU). Subcutaneous fat biopsy specimens were digitally scanned for calculation of mean fat cell area. All participants who had fat biopsy and CT data at baseline (n=54), undetectable viral loads on ART, and biopsy or CT data at week 96 (n=30) were included. At study entry (prior to starting ART), median age was 40 years, CD4+ T lymphocyte count was 219 cells/mm3, and BMI was 26.0 kg/m2; 89% of participants were male and 67% self-identified as Caucasian. Median subcutaneous abdominal fat quantity and density were 199 cm2 and -100 HU. Over 96 weeks of ART, fat quantity increased (+18%) and fat density decreased (-3%). Mean fat cell area correlated with fat density measured on CT scan both before and after ART and after adjusting for fat quantity, age, race, sex, CD4+ T lymphocyte count, and HIV-1 RNA. Therefore, subcutaneous fat density measured by CT scan served as an accurate representation of subcutaneous fat cell size in adults with HIV on and off ART, suggesting that CT is a useful tool for non-invasive assessment of fat quality. Further study of the use of CT-measured fat quality on health outcomes is indicated.

Lake JE, Moser C, Johnston L, Magyar C, Nelson SD, Erlandson KM, Brown TT, McComsey GA. CT Fat Density Accurately Reflects Histologic Fat Quality in Adults With HIV On and Off Antiretroviral Therapy. Journal of Clinical Endocrinology & Metabolism 2019 Oct 1;104(10):4857-4864. doi: 10.1210/jc.2018-02785

1077HS/4: Predictors of Viremia in Postpartum Women on Antiretroviral Therapy
Undetectable viral load is associated with optimal health outcomes for people living with HIV. However, among women living with HIV who have recently given birth and are on ART, there are high rates of viremia, which typically occurs because women are struggling to take their medication every day. 1077HS/4 sought to better understand the characteristics of post-partum women with viremia in order to understand how best to support their adherence.

The study enrolled a subset of women who were part of the PROMISE study. PROMISE was originally designed during the era when women living with HIV were instructed to take ART during pregnancy and then stop after delivery if they had strong immune systems. PROMISE enrolled postpartum women with good immune function (CD4 counts > 400 cells/mm³) from 56 sites in Argentina, Botswana, Brazil, China, Haiti, Peru, Thailand, and the U.S. between December 2011 and November 2014. Women were randomly assigned to continue their ART (828 women) or discontinue it (825 women) under their providers’ supervision. When deemed medically necessary, women who discontinued treatment were put back on ART. 1077HS/4 looked at a subset of PROMISE women who were on ART during study follow-up: those in the group asked to continue ART (802 women) and those who discontinued ART but later restarted for a medical reason (137 women). Over 144 weeks of follow-up, researchers evaluated the frequency with which women experienced viremia (>1000 copies/mL), their ART adherence (self-reported missed doses), and their self-reported health.

The study found that viremia was common among all women who had recently given birth who were continuing on ART (~20%) and that most viremia was due to difficulty taking medication rather than drug resistance (only 12% had viremia due to resistance). Younger women, women who started ART later in pregnancy, and women enrolled from the South American/Caribbean region had the highest rates of viremia during follow-up. Women in the group who discontinued ART and restarted later had very similar rates of viremia compared to women who continued ART after delivery. Among women with viremia, many never returned to an undetectable viral load during the follow-up period. Information from this study and others like it can be used to design programs to support the adherence of post-partum women on ART and tailor these adherence interventions to women’s unique needs.

Hoffman R, Warshaw M, Amico KR, Pilotto JHdS, Masheto GR, Achalapong J, Machado ES, Chokephaibulkit K, Duarte G, Joao EC, Graham K, Knapp KM, Stek AM, Scott GB, Coletti A, James Loftis AM, Chakhtoura N, Currier JS. Predictors of Viremia in Postpartum Women on Antiretroviral Therapy. JAIDS 2019 Oct 22. doi: 10.1097/ QAI.0000000000002228. [Epub ahead of print]

ACTG SITE SPOTLIGHT – COMING SOON!

Starting in January 2020, each newsletter will highlight one ACTG site from around the world. Keep an eye out for an email from us requesting information!

From left to right; Irma Febo, MD, Jorge Santana, MD, and Carmen D. Zorilla, MD
INVESTIGATOR HIGHLIGHT

IUPR-CTU Leadership Team

The Integrated University of Puerto Rico Clinical Trials Unit (IUPR-CTU) is a coalition/merger of independent clinical trials sites originally associated with the Adult ACTG (CRS 5401) and Pediatric ACTG (CRS 6601).The infrastructure and collaborative research capacities facilitated a quick response during the Zika epidemic in Puerto Rico in 2016 to enroll pregnant women in the ZIP-Zika in Infants and Pregnancy study.

Carmen D. Zorrilla, MD, the PI, has been the leader of this CTU for the past three funding cycles. Her leadership style is collaborative and has promoted the integration of administrative, laboratory, pharmacy, and community engagement activities for the benefit of the CTU. For more than two decades she has been working with her two scientific partners: Irma Febo, MD (IMPAACT site leader) and Jorge Santana, MD (ACTU site leader). This partnership is the outcome of having collaborative work on specific issues and populations that required distinctive expertise.

Dr. Zorrilla, Professor of Obstetrics and Gynecology at the UPR School of Medicine and CEMI Director, was one of the leaders in the implementation of the PACTG 076 in Puerto Rico, a study that changed the course of HIV infection for children and pregnant women. Puerto Rico established its public policy of offering free ZDV to pregnant women just one month after the study was halted for ethical reasons on February 1994, due to the efficacy of ZDV. Dr. Zorrilla was instrumental in this policy change and ever since has worked on HIV-related scientific research. Having established the first longitudinal clinic for women living with HIV in Puerto Rico in 1987, Dr. Zorrilla’s pioneering research includes behavioral interventions and clinical trials with people living with and vulnerable to HIV, including pregnant women.

Dr. Febo, Director of the Pediatric HIV/AIDS Research Program and Site Leader of the IMPAACT CRS of the IUPR-CTU, provides leadership in pediatric and adolescent care, research, and prevention. Drs. Febo and Zorrilla’s work and interest overlap with pregnant women, adolescents, and youth who acquired HIV through perinatal transmission. This has facilitated the integration of research through NIH funding and service through HRSA Ryan White funding. Making clear that functions are not overlapping, participants are provided services and access to clinical research.

Dr. Santana, Professor of Medicine and Infectious Disease at UPR School of Medicine and Fellow of the Infectious Disease Society of America and American Academy HIV Medicine, brings expertise in adult infectious diseases and co-morbidities. In the last several years, his interest has flourished on topics related to chronic immune activation, inflammation, and cure. He has been the site (ACTU) Investigator and Director for the past 21 years, an active member of ACTG’s OpMan BONE committee, and a three-term member of the Underrepresented Population committee, assuring participation of women and minority within the ACTG Network in order to maintain active participation and minimize health, sex, and gender disparities.

CAB MEMBER HIGHLIGHT

Julio Barros, Brazil

Julio Barros, who lives in Porto Alegre, Brazil, joined the ACTG in 2000 because he saw a need for community participation in clinical research. “My city has the highest incidence and prevalence of HIV in the country even though access to healthcare is universal and HIV treatment and medicines are free. Unfortunately, there are no prevention campaigns.”

He also identifies treatment for tuberculosis (TB) as one of the most important treatment issues for his community.

Julio hopes that his work with ACTG will be remembered as part of a global effort towards finding a cure for HIV.

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 Executive Director Alexis Sexton.