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 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.