Landmark trial demonstrates effectiveness 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!

Health Topics: 

A year-long extended release nanoformulated cabotegravir prodrug


Kulkarni TA, Bade AN, Sillman B, et al. A year-long extended release nanoformulated cabotegravir prodrug. Nat Mater. 2020;19(8):910-920. doi:10.1038/s41563-020-0674-z

Long-acting cabotegravir (CAB) extends antiretroviral drug administration from daily to monthly. However, dosing volumes, injection site reactions and health-care oversight are obstacles towards a broad usage. The creation of poloxamer-coated hydrophobic and lipophilic CAB prodrugs with controlled hydrolysis and tissue penetrance can overcome these obstacles. To such ends, fatty acid ester CAB nanocrystal prodrugs with 14, 18 and 22 added carbon chains were encased in biocompatible surfactants named NMCAB, NM2CAB and NM3CAB and tested for drug release, activation, cytotoxicity, antiretroviral activities, pharmacokinetics and biodistribution.

Development of a long-acting direct-acting antiviral system for hepatitis C virus treatment in swine


Verma M, Chu JN, Salama JAF, et al. Development of a long-acting direct-acting antiviral system for hepatitis C virus treatment in swine. Proc Natl Acad Sci U S A. 2020;117(22):11987-11994. doi:10.1073/pnas.2004746117

Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis worldwide and kills more Americans than 59 other infections, including HIV and tuberculosis, combined. While direct-acting antiviral (DAA) treatments are effective, limited uptake of therapy, particularly in high-risk groups, remains a substantial barrier to eliminating HCV. We developed a long-acting DAA system (LA-DAAS) capable of prolonged dosing and explored its cost-effectiveness. We designed a retrievable coil-shaped LA-DAAS compatible with nasogastric tube administration and the capacity to encapsulate and release gram levels of drugs while resident in the stomach. We formulated DAAs in drug-polymer pills and studied the release kinetics for 1 mo in vitro and in vivo in a swine model. The LA-DAAS was equipped with ethanol and temperature sensors linked via Bluetooth to a phone application to provide patient engagement. 

Emerging Technologies for New Solutions in Global Health Priority Areas (Round 23)

Grant Source: 

A set of rapidly-evolving technologies is changing the world and expanding the realm of the possible. These emerging technologies include – but are not limited to – artificial intelligence, materials science, wearable sensors, synthetic biology, nanotechnology, microscopy, augmented and virtual reality, geospatial mapping, robotics, and DNA sequencing. 
DEADLINE: 10 APR 2019 - 11:30AM PDT

Health Topics: 

Accelerating impact of long-acting technologies in low- and middle-income countries (LMICs)

Grant Source: 

Safe and efficacious medicines are available for the prevention and treatment of major diseases, but their effectiveness can be compromised by poor treatment completion. Lack of adherence can worsen clinical outcomes, leading to increased mortality, persistent transmission and increased drug resistance in the case of antimicrobials and antivirals. Analyses of treatment and prevention of HIV, malaria, and TB within public health programs show wide disparities in rates of completion, especially among specific populations and regions.

Application Deadline: 23 April 2019

Predicting drug-drug interactions between rifampicin and long-acting cabotegravir and rilpivirine using PBPK modelling


Rajoli RKR, Curley P, Chiong J, et al. Predicting drug-drug interactions between rifampicin and long-acting cabotegravir and rilpivirine using PBPK modelling. J Infect Dis. 2019 May 5;219(11):1735-1742. doi: 10.1093/infdis/jiy726. PMID: 30566691; PMCID: PMC6500558.

Cabotegravir and rilpivirine are two long-acting (LA) ARVs that can be administered intramuscularly (IM); their interaction with rifampicin, a first-line anti-TB agent, has not been investigated. The aim of this study was to simulate and predict DDIs between these LA ARV agents and rifampicin using PBPK modelling.

Modelling the long-acting administration of anti-tuberculosis agents using PBPK: a proof of concept study


Rajoli RKR, PodanyAT, Moss DM, et al. Modelling the long-acting administration of anti-tuberculosis agents using PBPK: a proof of concept study. Int J Tuberc Lung Dis. 2018 Aug 1;22(8):937-944. PMID: 29991405; PMCID: PMC6166436.

Anti-tuberculosis formulations necessitate uninterrupted treatment to cure tuberculosis (TB), but are characterised by suboptimal adherence, which jeopardises therapeutic efficacy. Long-acting injectable (LAI) formulations or implants could address these associated issues.

niazid, rifapentine, bedaquiline and delamanid—in adults for treatment for latent tuberculous infection (LTBI).