WORLD AIDS DAY - A Letter from ACTG Leaders
To the ACTG community,
World AIDS Day is an important opportunity for everyone to be reminded about the global impact of HIV and for the ACTG to provide our community with insights into work we have conducted over the last year (there’s been lots of it!). We are proud to have welcomed new sites into the network, including CAPRISA eThekwini CRS (Durban, South Africa), Nutricion-Mexico CRWS (Mexico City, Mexico, highlighted in this newsletter), and Yen Hoa Health Clinic CRS (Hanoi, Vietnam, highlighted in this newsletter). We recently held elections and are rotating leadership across our scientific committees this month. We are grateful to the outgoing TSG leaders for their service to the ACTG and contributions to our work, including
Drs. Gavin Churchyard, Ron Ellis, Susanna Naggie, Turner Overton, and Pablo Tebas.
COVID-19 has had a tremendous impact on our efforts over the last 21 months, but we have persisted and seen great progress in re-igniting our HIV research agenda. We have re-opened sites that previously had to be closed for safety reasons and opened new studies across our scientific agenda. After almost two years, clinical trial enrollment is increasing. We will not let COVID-19 halt our far-reaching HIV/TB/hepatitis agenda!

We are also proud of the tremendous impact the ACTG has had on COVID-19 through our efforts around ACTIV-2 (A5401). We added seven new agents to the study over the course of 2021, three of which have graduated from phase 2 to phase 3. These include a combination monoclonal antibody infusion (BRII-196/BRII 198), a polyclonal antibody infusion (SAB-185), and an inhaled formulation of interferon beta (SNG001). ACTIV-2 has enrolled more than 3,500 people, half of whom are people of color. And we were proud to present interim data on BRII-196/BRII-198 at IDWeek earlier this fall. We have initiated work on new trials of promising oral antiviral agents against COVID-19 and we look forward to providing updates on those efforts in the coming months. This progress would not be possible without the dedicated efforts of the entire ACTIV-2 team under the leadership of Drs. Davey Smith and Kara Chew.
We have also shared a number of important study results over the last year. In June, the New England Journal of Medicine published a paradigm-shifting study demonstrating the feasibility of decreasing the length of TB treatment by one-third – a profound advancement in the management of a disease that continues to proliferate globally. JAMA Network Open published a study from REPRIEVE on cardiovascular risk among people living with HIV finding that approximately half of study participants who were considered by traditional measures to be at low-to-moderate risk of future heart disease had atherosclerotic plaque in their coronary arteries. We continue to advance the understanding of the HIV reservoir and we opened our first combination study of HIV reservoirs and functional cure that include dual broadly neutralizing antibodies.

We started enrolling four new studies, focusing on a variety of issues relevant to people living with HIV, TB, and COVID-19. The studies focus on HIV cure research, weight gain for people on ART, immune responses after COVID-19 therapy and vaccine, and a three-month TB treatment.
This year hasn’t been an easy one, but it has provided an opportunity for the ACTG to demonstrate resilience and advance our research agenda. On this World AIDS Day, we want to express our appreciation for all the hard-working staff, investigators, and community members who have demonstrated remarkable flexibility and an unflinching commitment to end both HIV and COVID-19. We look forward to continued collaboration and engagement with all of you, as we work toward a better future for people living with HIV, TB, hepatitis, and COVID-19.
Judy and Joe

Press Releases and Announcements
The ACTG congratulates the winners of the 2021 ACTG Awards! The winners were announced on November 9, 2021 at the 2021 ACTG Leadership Retreat in Los Angeles, California. If you missed the emotional live presentation, you can view the presentation and listen to remarks from the recipients here!
  • The 2021 James Hakim International Investigator Mentor Award recipient is Patrice Severe, MD from our Les Centres GHESKIO CRS in Haiti.
  • The 2021 Kevin Robertson Memorial Award recipient is Scott Letendre, MD from our UCSD Antiviral Research Center CRS.
  • The 2021 Charles van der Horst Humanitarian Award recipient is Shahin Lockman, MD, MSc from our Botswana-Harvard School of Public Health-AIDS Initiative Partnership CTU.
  • The 2021 John Carey Young Investigator Award recipient is Cecilia Kanyama, MBBS, FCP from our Malawi CRS.
  • The 2021 Constance B. Wofsy Women's Health Investigator Award recipient is Eileen Scully, MD, PhD from our Johns Hopkins University CRS.
  • The 2021 Donna Davis Community Award recipient is Martha Weaver from our Network Coordinating Center.

Last month, the ACTG announced the launch of A5404, a clinical trial studying how prior infection with SARS-CoV-2 and receiving either an investigational COVID-19 therapy or placebo/active comparator affects participants' immune responses to mRNA COVID-19 vaccines. Read more here.

Now enrolling: A5362 (CLO-FAST)! The ACTG announced the launch of A6362 (CLO-FAST), a clinical trial studying a three-month clofazimine- and high-dose rifapentine-containing treatment regiment for people with drug-susceptible tuberculosis. This is the first TB regimen based on preclinical evidence of effectiveness that is less than four-months long to be studied in a clinical trial! Read more here.

Congratulations to our very own ACTG Community Members, Danielle Campbell and David Jax Kelly for being recognized among POZ Magazine's Top 100 Black Advocates! Read more here.

In Memoriam

It is with heavy hearts and sincere sadness that we share the passing of Dr. Scott Hammer on Thursday, November 17. He was a long-time ACTG leader, investigator, and virologist who made significant contributions for more than 25 years. Dr. Hammer was a brilliant scientist who will be remembered for his kindness and generosity towards his colleagues. He will be sorely missed. We extend our deepest sympathy and condolences to his wife Susan, and to his colleagues at Columbia and around the globe.

Dr. Hammer began his ACTG service as the site leader at what was then the New England Deaconess Medical Center, a subunit of the Massachusetts General Hospital ACTU at the time. He was then the Columbia University CTU PI until June 2018 and also served as a PI mentor to the Durban CTU when it was onboarded in 2004 as one of ACTG’s first international sites.
“Scott took a chance as a new chief of infectious diseases and gave me a last-minute fellowship position at Columbia,” said Tim Wilkin. MD, MPH. “He launched my career and has been an ongoing mentor and role model for me. He encouraged me to think big and to be strategic about my career decisions. Scott exhibited a sustained dedication to mentoring new clinical researchers and supporting the advancement of women scientists. His work has changed the lives of millions of people living with HIV around the world.” 

Dr. Hammer served as a protocol chair, investigator, or virologist on nearly 50 ACTG protocols and sub-studies, including ACTG 175, the first clinical endpoint trial for dual therapy (which he co-chaired with the late Dr. David Katzenstein). He chaired the landmark ACTG 320 trial demonstrating the clinical benefit of triple drug therapy. Along with Dr. Katzenstein and Dr. Mary Albrecht, he co-chaired ACTG 364, a pivotal study in support of FDA approval of efavirenz. And along with Dr. John Mellors, he was the protocol chair for ACTG 398, which studied four different combinations of anti-HIV drugs for people with drug resistance. Dr. Hammer’s ACTG research resulted in more than 50 publications and numerous abstract presentations at major HIV/AIDS and infectious diseases conferences.

Dr. Hammer also served on numerous science and leadership committees over the years, including the ACTG Executive Committee, Performance Evaluation Committee, and Scientific Agenda Steering Committee and was the vice chair and later chair of the HIV Disease Research Agenda Committee, equivalent to a Transformative Science Group today. He was very thoughtful and fair in his committee contributions and deliberations and was an integral part of forming the robust site performance evaluation program we have in place. He served as a mentor and role model to many of us over the decades.

“Dr. Hammer was always very thoughtful and diplomatic in his approach when providing input to the committees and interacted in the same manner with support staff like myself, consistently kind and appreciative of our services,” said Lisa Patton, NCC.
Investigating the genetics of drug interactions with a long-acting contraceptive in women being treated for HIV and tuberculosis

Depot medroxyprogesterone acetate (D-MPA) is a long-acting injectable contraceptive used worldwide to prevent pregnancy. ACTG study A5338 previously evaluated the impact of D-MPA on women living with HIV in sub-Saharan Africa who were being treated for HIV (with efavirenz) and tuberculosis (with rifampicin and isoniazid) and receiving D-MPA. A5338 found that blood levels of MPA in some women would become too low to reliably prevent pregnancy before their next D-MPA dose. This finding was important but not surprising, as rifampicin and efavirenz both cause the liver to break down many drugs more quickly. The study team concluded that women receiving this combination of drugs should receive D-MPA more frequently than the usual 12-week interval.

To take study A5338 one step further, the research team asked whether an individual’s genetics affected how low their MPA levels went. The team expected women with genetic variants that increase efavirenz levels in their blood (because of a gene called CYP2B6) would have lower MPA levels (as efavirenz levels increase, the more the liver gets turned on to break down drugs). In fact, in an earlier ACTG study (A5316), this is exactly what was seen in women receiving hormonal contraceptives as a vaginal ring. The team also expected more dramatic effects in women with genetic variants that increased their isoniazid levels (because of a gene called NAT2). Unexpectedly, the women in study A5338 with genetic variants that increased their efavirenz levels (n=27) or their isoniazid levels (n=39) had MPA levels no different than women without these variants. This may be because rifampicin so strongly turned on their livers to break down drugs that higher efavirenz levels could not add to rifampicin’s effect. The conclusion was that knowing a person’s CYP2B6 or NAT2 genetics would not change D-MPA dosing in women receiving rifampicin, isoniazid, and efavirenz. This study highlights that additional genetic testing is not necessary among women to determine the ideal contraceptive dose.

Haas DW, Mngqibisa R, Francis J, et al. Pharmacogenetics of interaction between depot medroxyprogesterone acetate and efavirenz, rifampicin, and isoniazid during treatment of HIV and tuberculosis. Pharmacogenet Genomics. 2022;32(1):24-30. doi:10.1097/FPC.0000000000000448

Modern HIV medications do not change viral rebound timing during treatment interruption
While antiretroviral treatment (ART) has saved millions of lives, it cannot eradicate HIV. As such, finding a cure for HIV remains one of the highest priorities in HIV research today. There are many new HIV cure strategies currently being evaluated in clinical trials, but eventually, these strategies will need to be tested in treatment interruption studies in order to demonstrate that they can delay or suppress HIV rebound without HIV medications. To interpret the results of these treatment interruption trials, we need a clear understanding of what happens without an intervention. Most historical treatment interruption trials were performed with older ART regimens before the arrival of newer ones that are more potent and have improved tolerability and easier dosing, which promote better adherence. As a result, there is uncertainty as to whether modern ART regimens will achieve better viral suppression and potentially alter how quickly HIV rebounds after treatment interruption. In addition, while there is evidence that initiation of ART during early HIV infection may delay HIV rebound, this also needs to be confirmed in the era of modern ART.
In A5345, early- and chronic-treated participants on modern ART (almost all were on an integrase inhibitor-based therapy) interrupted their ART regimens and were intensively monitored. Participants restarted ART once their HIV viral load reached 1000 HIV-1 RNA copies/mL (which is known as HIV rebound). The timing of HIV rebound was compared to six historic ACTG treatment interruption studies. The study found that modern ART did not result in substantial changes in when HIV rebounded after treatment interruption. Interestingly, those who started ART during early (or acute) HIV infection had a significantly greater chance of remaining off ART 12 weeks after the treatment interruption. The results of A5345 demonstrates that while modern ART is insufficient for lowering the barrier to HIV remission, early ART initiation could be an important component of a comprehensive strategy towards an HIV cure. Additional laboratory studies are ongoing to determine whether there are HIV reservoir and immunology predictors of the timing of HIV rebound.

Li JZ, Aga E, Bosch R, et al. Time to Viral Rebound After Interruption of Modern Antiretroviral Therapies [published online ahead of print, 2021 Jun 12]. Clin Infect Dis. 2021;ciab541. doi:10.1093/cid/ciab541
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