ACTG Articles in HANC Newsletter

Following is a listing of articles submitted by the ACTG for inclusion in the Office of HIV/AIDS Network Coordination (HANC) monthly newsletter.

 

Submission for August 2019 newsletter

This month, we are highlighting the exciting presentations ACTG made at the recent International AIDS Society (IAS) meeting in Mexico City, July 21-24, 2019:

VRC 607/ACTG 5378 was featured as an oral presentation at IAS 2019 by Dr. Grace Chen and colleagues. A two-part study conducted by the Vaccine Research Center (VRC) and ACTG, VRC 607/ACTG 5378 investigated two CD4 binding site HIV-1 broadly neutralizing antibodies (bNAbs) in treatment naïve HIV-infected adults: VRC01LS (Part A) and VRC07-523LS (Part B). This is the first in-person trial conducted of these agents among people living with HIV, with previous studies restricted to pre-clinical evaluations or those in HIV-uninfected volunteers. The study evaluated the safety, tolerability, antiviral activity, and pharmacokinetic parameters of these bNAbs in 16 HIV-infected viremic adults between the ages of 18-70 years. Overall, both were safe and well-tolerated, with minimal side effects. Importantly, antiviral activity of ≥ 0.5 log was observed in 3/7 VRC01LS recipients and >1.2 log for 8/9 VRC07-523LS recipients in this small study, providing tantalizing hope for the efficacy of these novel agents as they advance into later stage trials.

The OPTIONS Study (A5241), which asked whether NRTIs are essential in salvage regimens, was presented as a poster at IAS 2019 by Dr. Rajesh Gandhi and colleagues. This study, which found that salvage regimens that did not include NRTIs gave similar rates of durable virologic suppression as those that included NRTIs, was also published in the Journal of Infectious Diseases in May. For more information on this important study, please read the summary that appeared in the June  HANC newslettter.

Submission for July 2019 newsletter

The ACTG annual meeting took place June 17-21 in Arlington, VA and drew more than 850 attendees. Highlights included robust discussions about the ACTG research agenda among international investigators, a workshop introducing new investigators to the ACTG and plenary sessions providing a sneak preview of new ACTG data that will be presented at the 10th IAS Conference on HIV Science, taking place in Mexico City in July.

In addition, our recent publication ACTG A5308 examined the effect of ART on virologic suppression, the viral reservoir, immune activation and quality of life in a group of elite controllers enrolled in the ACTG, in an attempt to answer the question of whether elite controllers require ART for secondary benefits, including control for low-level viral replication and reduction of inflammation. A5308 study was a prospective, open-label study of rilpivirine, emtricitabine and tenofovir disoproxil fumarate provided to ART-naïve HIV controllers (n=35) defined as having HIV RNA levels of <500 copies/mL off of therapy. The study found that ART was effective in increasing the proportion of individuals with undetectable residual viremia and decreasing the proportion of CD38+HLA-DR+CD8+ T cells (a marker of immune activation). Researchers also identified a modest but statistically significant improvement in self-reported quality of life. A5308 resolves the debate around the value of ART for elite controllers, by demonstrating the clinical benefits of ART in this population. Read more in Clinical Infectious Diseases 2019: ciz442 (Li J et. al)

The ACTG HIV Reservoirs Cohort Study (A5321) addressed the challenges of persistence in the nervous system. In this study, virally suppressed individuals with HIV taking long-term ART were tested for persistent HIV in their cerebrospinal fluid and underwent neurocognitive assessments, which included tests of memory, learning, motor function, and more. The study revealed that HIV DNA was detected in almost half of participants and was associated with poorer neurological and cognitive function. This persisted even after adjusting for participants’ age and the severity of immune suppression they had experienced in the past. The association between HIV genetic material in cerebrospinal fluid with poorer performance on cognitive tests suggests that there may be a link between HIV persistence in the brain compartment and the neurological complications that some people living with HIV experience. Further studies will help determine strategies to reverse this persistence and improve neurological functioning in patients with long-standing HIV. (Journal of Clinical Investigation 2019, in press; Spudich S, Robertson K, et al.)

Submission for June 2019 newsletter

The ACTG would like to highlight two recent publications of important ACTG studies:

The OPTIONS study (A5421) looked at whether NRTIs are a necessary component of salvage antiretroviral regimens. The study included more than 350 people with HIV who had received and developed resistance to a variety of medications. The trial, which lasted almost 2 years, showed that clinicians do not need to add NRTIs to salvage regimens, as long as the new regimen has a cumulative activity of 2 or more active medicines from other drug classes.
Salvage regimens that did not include NRTIs gave similar rates of durable virologic suppression as those that included NRTIs. This study changes the
dogma that NRTIs are necessary in a salvage regimen and has major implications for clinical care. The publication (Gandhi RT et cl.) and an accompanying editorial
(Hoenig M et al.) can be found in the Journal of Infectious Diseases 2019 May 28.

The MULTI-OCTAVE study (A5288) is one of the first studies to look at interventions for medication adherence in lower- and middle-income countries (LMICs) for individuals failing second line therapy. Study participants received and responded to a randomized cell phone-based adherence support intervention, first daily and then tapering down to once a week. The study showed a small (but not significant) benefit of a mobile phone-based intervention for ART adherence on the primary outcome of achieving virological suppression at 48 weeks, and a small (and statistically significant) effect on the outcome of time to virological failure. The authors conclude that adherence behavior is challenging and that, while two-way text messaging might help given the effects on virological failure, more research on this and other adherence support strategies are needed. Read more in Lancet Digital Health 2019; 1: e26–34 (Gross R et al.).

Submission for May 2019 newsletter

4/5/2019
For this month’s HANC newsletter, the ACTG is excited to introduce a new initiative within the network. The series —   “They Became My Family” — is a new digital archive starting up this month spotlighting the community members that are a vital component of the ACTG. Spearheaded by ACTG Community Scientific Subcommittee member Liz Barr, “They Became My Family” is named for a quote describing the ACTG community from the late Sharon Maxwell. As a long-time member of the ACTG Global Community Advisory Board and the Legacy Project’s Women’s HIV Research Collaborative, Ms. Maxwell worked to end HIV stigma, especially as it affected women and people living in rural communities.

“They Became My Family” offers members of the ACTG community the opportunity to share their experience and commitment to participating in the network, in their own words. Participants are asked to submit some type of self portrait (photograph or drawing) and to answer a few questions about their work with the ACTG, the community they represent, what they’ve been able to do, and their hopes for the future. While each profile follows roughly the same format, the end results are as moving and diverse as the ACTG community itself.

“They Became My Family” will be a featured part of the updated ACTG website, premiering later in 2019.

 

Submission for April 2019 newsletter

4/5/2019
ACTG researchers gave 11 oral and 19 poster presentations at CROI 2019 (Seattle, March 4-7) on topics such as short-course therapy for people with MDR-TB; advances and challenges in HIV cure research; interactions between ARVs and hormonal contraception; cognitive function, obesity and long-term HIV infection; predictors of virologic outcome and failures; and many other research topics. A complete list of ACTG presentations, with a short synopsis, author list, and links to posters or presentation webcasts is available here.

ACTG researchers Katharine Bar, Sara Bares, Judith Currier, Kelly Dooley, Kristine Erlandson, Monica Gandhi, Sara Gianella, Timothy Henrich, Peter Hunt, and Gary Maartens helped to explain the conference research and its implications in more than two-dozen media reports filed from the Seattle meeting, available here.

In other ACTG news, A5279, the BRIEF study, was published March 14 in the New England Journal of Medicine, along with an accompanying editorial, “Ending Tuberculosis Through Prevention.” This important trial is likely to have a major impact on global TB control guidelines and the lives of people living with HIV. Congratulations to the study team and to the 3,000 volunteers whose tireless work made this critically important research finding possible.

 

Submission for March 2019 newsletter

3/1/2019
This month, we’d like to highlight a few of the ACTG’s 11 oral and 19 poster presentations at CROI 2019 (Seattle, March 4-7), including following:

84LB. QT EFFECTS OF BEDAQUILINE, DELAMANID OR BOTH IN MDR-TB PATIENTS: THE DELIBERATE TRIAL (presented by ACTG investigators Dr. Kelly Dooley and Gary Maartens). Bedaquiline and delaminid, the first two novel medications for MDR-TB to be developed in decades, generated extensive excitement when released. However, there is a lingering concern about overlapping toxicities with the two medications, specifically prolongation of the QT interval. This abstract resolves the debate.

82. EARLY BACTERICIDAL ACTIVITY OF HIGH-DOSE ISONIAZID AGAINST MULTI DRUG RESISTANT TB (presented by Dr. Dooley). High-dose isoniazid (INH) 10-15 mg/kg was recently left off of the World Health Organization guidelines for multidrug-resistant TB due to lack of data about bacteriocidal killing against TB with typical patterns of INH resistance. This abstract provides pivotal data that could impact guidelines.

While at CROI (or through the conference webcasts), we also invite you to hear important new data from ACTG studies on the interactions between hormonal contraceptive and HIV-TB medications (abstract 78, Dr. Rosie Mngqibisa); the risk of weight gain with integrase inhibitors (abstract 669, Dr. Jordan Lake); the impact of cardiovascular risk scores on neurocognitive function (abstract 128, Dr. Felicia Chow); the impact of obesity on cognitive function (abstract 129, Dr. Jeremiah Perez); sex differences on 3rd line ART (abstract 518, Dr. Catherine Godfrey); the impact of pharmacogenetics on drug-drug interactions between
efavirenz and hormonal contraceptives (abstract 52, Dr. David Haas); and important abstracts on cure including the effects of sirolimus (abstract 131, Dr. Timothy Henrich) and romidepsin (abstract 26, Dr. Deborah McMahon); along with many other ACTG studies.

Finally, we’d like to announce the upcoming publication of the A5279 study (the BRIEF TB study) slated for March 14th in the New England Journal of Medicine. This pivotal phase 3 trial showed that a one-month antibiotic regimen with rifapentine and isoniazid to prevent active tuberculosis (TB) disease was at least as safe and effective as the standard nine-month therapy with isoniazid for people living with HIV. This important trial is likely to change the standard of care for preventative therapy for TB worldwide.

 

Submission for January 2019 newsletter

1/8/2019
The AIDS Clinical Trials Group (ACTG) would like to highlight the upcoming opening of a landmark study on HIV treatment.  ACTG’s new LATITUDE study (Long-Acting Therapy to Improve Treatment SUccess in Daily LifE) (ACTG 5359) is an innovative study that may shift the paradigm for treating participants with the most difficulty adhering to daily medications.  This population may benefit from a novel approach to treating HIV by using injectable agents administered once monthly in the clinic instead of requiring daily consumption of medications. These injectables could be life-saving for participant with adherence struggles. LATITUDE (A5359) will compare treatment outcomes among participants with a past history of non-adherence and virologic failure randomized to once monthly long-acting injectable rilpivirine plus cabotegravir versus standard-of-care daily combination ART (SOC). Participants will be randomized to one of the two strategies after achieving short-term virologic suppression with the help of milestone-driven financial incentives, and will be followed for 52 weeks with the SOC arm offered open-label injectable ART thereafter for another 52 weeks. LATITUDE will begin enrolling soon at 35 sites across the U.S. To learn more about the upcoming LATITUDE opening, visit ACTGNetwork.org, or contact Mwenda Kudumu at MKudumu@s-3.com.

 

Submission for December 2018 newsletter

11/28/2018
The AIDS Clinical Trials Group (ACTG) is pleased to highlight a few network publications over the past month; they include a study looking at the effects of a broadly neutralizing antibody (bnMAb) against HIV on measures of HIV persistence and a study evaluating the effects of a two-drug therapy combination of HIV (dolutegravir plus lamivudine) on genital shedding of HIV RNA.

The concept behind the first study (Riddler SA et al.  Open Forum Infect Dis. 2018 Oct 20) is to examine the effects of a monoclonal antibody against HIV on measures of HIV persistence. Monoclonal antibodies have been developed as treatments for a variety of conditions including cancer and autoimmune disorders; antibodies specifically directed at the HIV-1 envelope can promote antibody-dependent cell-mediated cytotoxicity and could enhance killing of HIV-1 expressing cells.  This study examined the effects of a potent broadly neutralizing monoclonal antibody (bnMAbs) called VRC01 on measures of the latent reservoir in a randomized placebo-controlled clinical trial (the ACTG 5342 study). In A5342, participants on suppressive ART were randomized to receive two infusions of VRC01 versus placebo (saline). Although the infusions were safe and tolerated, there was no significant difference in residual plasma viremia, the cell-associated HIV-1 RNA/DNA ratio, or stimulated virus protection from CD4+ T cells in the two arms. This was an important negative study and the activity of more potent and broader bnMAbs, along with bnMAb combinations, warrant further study.

The second study (Gianella S. JAIDS 2018 Dec 15) asked the important question on whether genital shedding of HIV RNA was the same with two-drug ART therapy versus three-drug ART given the increasing interest in two-drug therapy.  Investigators studied participants from the ACTG 5353 trial, which examined outcomes on two drug therapy with dolutegravir (DTG) + lamivudine (3TC) and another trial (ASPIRE) where individuals were simplified from a three-drug regimen to DTG plus 3TC.  In this pilot study of 51 adults living with HIV, the frequency of genital HIV RNA shedding (with virologic suppression in the blood) was similar between those who were on standard three-drug ART and those who were on DTG+3TC as initial or maintenance therapy. This study thereby provides some comfort that genital HIV shedding is not increased in participants on simplified 2-drug therapy, although further study is necessary.

 

Submission for November 2018 newsletter

10/31/2018
This month the AIDS Clinical Trials Group (ACTG) launched enrollment for a long-awaited study, specifically A5360: A Single-arm Study to Evaluate the Feasibility and Efficacy of a Minimal Monitoring Strategy to Deliver Pan-genotypic Ribavirin-free HCV Therapy to HCV Infected Populations who are HCV Treatment Naïve with Evidence of Active HCV Infection or The MINMON StudyGlobally, nearly 71 million people have chronic HCV, of whom an estimated 4-5 million also have HIV. In this context, there is an urgent need for advances in treatment delivery.  In some parts of the world, the healthcare system itself  - through requiring frequent visits and laboratory monitoring during HCV treatment - can lead to barriers to HCV treatment with the new easy-to-take once a day treatments for HCV cure. The basic premise of the study is to eradicate all of these healthcare system barriers.  In A5360, patients (n=400) will be provided HCV treatment with sofosbuvir/velpatasvir (Epclusa) for 12 weeks without any traditional laboratory or clinical monitoring or planned visits. Enrolling sites will be based in Africa, Brazil, India, Thailand and the United States, with two-thirds of participants being enrolled at international sites. Following HCV treatment, participants will be followed for an additional 72 weeks to assess the long-term outcomes related to HCV and liver disease, including the incidence of HCV reinfection. Study investigators hypothesize that this “minimal monitoring” for HCV treatment outcomes will result in more cost-efficient and effective paradigms in HCV treatment management, expanding the number of people who can achieve HCV cure worldwide.

The ACTG is also pleased to announce that the Tuberculosis Trials Consortium (TBTC) Study 31/ ACTG A5349 study completed participant enrollment in October.  This important study will examine the efficacy of a shorter 4-month course of treating pulmonary tuberculosis (TB) with a rifapentine-containing regimen compared to the traditional 6-month course of TB therapy.

The AIDS Clinical Trials Group (ACTG) would like to highlight a few of its publications over the past two months, including a study on parenting desires among men and women who have sex with women in A5257 (OFID Sept 15, 2018), a study showing the predictive utility of hair concentrations of antiretrovirals (ARVs) on virologic outcomes in A5257 (Clin Infec Dis Sept 3, 2018), post-treatment control of virologic suppression (J Infec Dis Aug 6, 2018), and neuropsychological manifestations of TB infection in the setting of HIV in A5199 (Clin Infect Dis Aug 20, 2018).

 

Submission for October 2018 newsletter

10/1/2018
The first study explored parenting desires to have children in the future among people living with HIV of reproductive age starting their first antiretroviral therapy (ART) regimen in A5237, a large trial among treatment-naïve individuals conducted throughout the U.S. The study found that women, men who have sex with women and MSM all had a similar desire to have children in the future (around 40%) both prior to starting ART and after 96 weeks, although there were some differences in factors leading to this desire in the 3 groups. Bottom line: Ongoing assessment of parenting goals for both men and women in HIV care is critical. The second study was conducted in the same ACTG trial (A5257) where participants were randomized to atazanavir/r, darunavir/r or raltegravir as first-line therapy. Hair samples were collected from a subset of participants and analyzed for concentrations of the relevant ARV. Multivariate proportional hazards regression model showed that lower hair ARV concentrations were strongly independent predictors of virologic failure (HR 2.43 (1.96-3.13, p <0.001 higher risk of VF for every 2-fold decrease in hair level), showing this predictive power of hair levels in a clinical trial for the first time. Bottom line:  Hair levels of ARVs can be used to assess adherence in clinical treatment trials and should be explored as a tool to avert virologic failure. The third study looked at participants across 8 ACTG trials (A371, A5024, A5068, A5102,  A5130, A5170, A5187, and A5197) who were HIV posttreatment controllers, rare individuals who start ART, but maintain HIV suppression after treatment interruption. Of the 67 posttreatment controllers identified, 38 initiated ART during early HIV infection (13% vs 4%, P < .001), with those early starters frequently characterized by early transient viral rebound and heterogeneous durability of HIV remission. Bottom line: Posttreatment control was more commonly identified amongst early treated individuals, which both informs mechanisms and how clinical trials of HIV remission should be designed. The fourth study looked at compared neurological and neuropsychological (NP) test performance of people living with HIV in resource-limited settings treated with three WHO recommended ART regimens (A5199 study).  Among 860 participants, those who had concomitant TB (either pulmonary or extrapulmonary, only 2 of 84 TB cases were CNS TB), those with TB co-infection had significantly poorer performance on fine motor skills, were >9x as likely to report a decreased quality of life, and 8x as likely to report loss of productivity. Bottom line: TB co-infection still carries significant morbidity in those living with HIV, including in neurological and NP function, and should be targeted avidly for prevention. 

 

Submission for September 2018 newsletter

8/29/2018
The AIDS Clinical Trials Group (ACTG) highlights the A5263 study oral abstract presented during the “Non-communicable diseases: Continued challenges” session at the AIDS 2018 meeting in Amsterdam.  This multinational trial was joint sponsored by the ACTG and the AIDS Malignancy Consortium and co-chaired by Drs. Margaret Borok-Williams and Susan Krown. The purpose of this trial was to evaluate the safety and efficacy of an oral etoposide chemotherapeutic regimen for advanced Kaposi’s Sarcoma (KS) in resource-limited settings (given that an oral regimen would provide significant logistical advantages) to intravenous (IV) bleomycin and vincristine (a less expensive option) to IV paclitaxel (the standard of care in resource-rich settings), all co-administered with antiretroviral therapy.  The oral etoposide and IV bleomycin/vincristine arms were both closed early due to their inferiority compared to the IV paclitaxel arms in terms of week 48 progression free survival (PFS); PFS rates were 19%, 43% and 63%, respectively. This trial establishes definitively the need for IV paclitaxel as the standard of care for advanced AIDS-associated KS in all settings and should urge an enhanced cancer therapeutic infrastructure and accessibility to essential chemotherapeutic agents worldwide.