Convened June 22-24, 2021, the 2021 virtual meeting of the International Maternal Pediatric Adolescent AIDS Clinical Trials Network highlights the latest updates and exciting science in the field, and includes sessions from JHUBI-CTU Co-PIs Drs. Amita Gupta and Charles Flexner. View Video Presentations
This World AIDS Day, HIV/AIDS researchers at Johns Hopkins Medicine learned that they now have an enhanced opportunity to help move the world toward a day when that observance is rendered obsolete. The National Institutes of Health (NIH)’s National Institute of Allergy and Infectious Diseases (NIAID) announced Dec. 1, 2020, that Johns Hopkins Medicine will receive five of the seven-year grants awarded to 35 U.S. and international institutions to operate clinical trial units (CTUs) and coordinate HIV/AIDS clinical trials in four federally funded networks.
The three CTU grants and two leadership awards for Johns Hopkins Medicine are the most given to any one institution.
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Publication: AIDS Clinical Trials Group
WORLD AIDS DAY - YEAR IN REVIEW December 1st marks World AIDS Day. For 32 years, this day has provided an opportunity for the world to reflect on the ongoing HIV/AIDS pandemic. In 2019, 38 million people were living with HIV/AIDS, and 1.7 million people were newly infected. Though 2020 drew HIV researchers to expand their work to address the COVID-19 pandemic, our HIV efforts have not ceased. To the contrary, the ACTG has continued to advance HIV research and clinical trials amidst the challenges of initial research study closures, social distancing, acquiring proper PPE, and quarantining. We are pleased to announce that the ACTG was re-funded for a new grant cycle for seven years starting today, World AIDS Day 2020. In this new grant cycle, our goals are to continue our efforts to cure HIV and Hepatitis B, shorten treatment for TB and find new therapies for drug-resistant TB, and test novel antiretroviral therapies and test strategies to improve long-term outcomes for people with HIV.
In December’s newsletter, we reflect on the progress we have made over the past year in HIV research, despite the challenges posed by COVID-19. We highlight some of ACTG’s major publications over the past year (although we sadly could not highlight all of the important publications from the ACTG in 2020 in this short newsletter, please click here to read more). Our network has found balance among the chaos and continues to instill hope in our community, despite overwhelming loss. We are grateful to everyone (investigators, site staff, community advisory board members) who has stepped up to the challenge and gone above and beyond for study participants. The strides we have made as a network keep us hopeful for the future of HIV/AIDS research. More ACTG Newsletter articles here
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!
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NIH Awards Johns Hopkins Baltimore-Washington-India Trials Group $460,679 in Supplemental COVID-19 Funding
On June 25, 2020, the Johns Hopkins Baltimore-Washington-India Clinical Trials Unit (BWI-CTU) received notification from the NIH approving supplemental funding to conduct COVID-19-related research at the Johns Hopkins (Baltimore) and Whitman Walker Health (Washington, DC) Clinical Research Sites. Led by Drs. Charles Flexner and Amita Gupta, the BWI-CTU supports high quality HIV-related treatment and prevention research at the two domestic sites and at the Byramjee Jeejeebhoy Government Medical College in Pune, India. The supplement is leveraging existing HIV research infrastructure and personnel resources for DAIDS-sponsored COVID vaccine and monoclonal antibody prevention trials that will include both HIV seropositive and seronegative participants. Activities supported involve preparing the two domestic sites to conduct COVID, and include community outreach and staff safety training. Partnering in the effort is the Johns Hopkins Center for Immunization Research. which will conduct vaccine trials beginning in July 2020.
The Johns Hopkins University Clinical Research Site (JHU CRS) and the Whitman Walker Health (WWH) have highly experienced and innovative leaders in anti-infective research and have a long and successful record of HIV and viral hepatitis clinical research implementation. Co-PI Dr. Charles Flexner noted the impressive reach the domestic CTU sites offer for such research: “The health systems that are supported by JHU and partner institutions currently provide medical coverage for more than half of all adult residents in the state. This includes having a physical presence in every major population center in the state, including the metropolitan Washington, DC, counties -- where nearly half of the state’s COVID cases have occurred. This is a great opportunity to swiftly leverage our existing resources in the search for COVID treatment and prevention strategies for both HIV positive and HIV negative patients.”
Publication: ACTG Network Newsletter
The Byramjee Jeejeebhoy Government Medical College–Johns Hopkins University (BJGMC-JHU) research partnership was established in 2000 to conduct the multi-country Six Weeks Extended Nevirapine (SWEN) trial to reduce HIV transmission through breastfeeding. The results of that trial led to changes in the World Health Organization’s clinical care guidelines. Capitalizing on the team’s success and the infrastructure established, the research partnership continued and has grown exponentially. With clinical operations based at BJGMC in Pune, India, the BJGMC-JHU CRS is now a member of the Baltimore-Washington-India Clinical Trials Unit (BWI-CTU), which includes a CRS at Johns Hopkins University (Baltimore) and at Whitman-Walker Health (Washington, DC). ACTG trials represent a significant portion of our research portfolio. We’re proud that our work is improving disease outcomes for patients in our own community and around the world.
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The COVID-19 pandemic presents real challenges for research teams around the world conducting clinical trials. The experience with tuberculosis studies underway at the Byramjee Jeejeebhoy Government Medical College-Johns Hopkins University Clinical Research Site (BJGMC-JHU CRS) in Pune, India, required swift action, agility, and innovation in ensuring that study participants continue to receive lifesaving care in the midst of a national lockdown.
The WHO has prioritized TB preventive therapy, including for household contacts of people with multidrug-resistant tuberculosis (MDR-TB), as a key strategy for controlling the epidemic. One study to prevent MDR TB among household contacts of confirmed cases currently underway at the BJGMC-JHU CRS is a multinational, phase 3, randomized clinical trial to compare 26 weeks of Delamanid (DLM) versus 26 weeks of Isoniazid (INH) for preventing confirmed or probable active TB in high-risk household contacts. For this trial, titled Protecting Households on Exposure to Newly Diagnosed Index Multidrug-Resistant Tuberculosis Patients (or PHOENIx), 19 index MDR-TB cases and 12 household contacts are enrolled.
Participants on study routinely receive enough medication to last until their next scheduled clinical visit. With visits cancelled due to the lockdown, and with recovery from COVID-19 likely to be prolonged, the PHOENIx Team needed to find alternate ways to distribute medication. Mail delivery was not an option, and asking research participants to pick up medication from the CRS or at designated locations within the community was deemed too risky.
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“A woman is more likely to develop tuberculosis (TB) in the first 90 days after she has a baby than at any other time in her life, especially if she has HIV,” Jyoti S. Mathad, MD, MS, assistant professor of medicine, obstetrics and gynecology, at Weill Cornell Medical College, told Healio. “WHO currently recommends that all people with HIV, including pregnant women, take medications to prevent TB, but a recent trial raised concerns about the most common regimen used during pregnancy: 6 months of daily isoniazid. That's a problem, because the more cutting-edge treatments, such as 3 months of weekly isoniazid and rifapentine (3HP), which has improved safety and adherence in nonpregnant people, has not been tested at all in pregnant women.”
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Publication: Johns Hopkins Center for Clinical Global Health Education
In a study published by The New England Journal of Medicine today, Dr. Amita Gupta and colleagues found evidence to suggest that administering isoniazid preventive therapy (IPT) to prevent tuberculosis among HIV+ pregnant women who are taking antiretroviral therapy (ART) offered no benefits over beginning IPT at 12 weeks after delivery. Moreover, IPT during pregnancy is associated with higher adverse composite pregnancy events, including higher rates of low birth weight, preterm birth, stillbirth, and congenital anomalies. The World Health Organization’s guidelines for preventing TB in HIV+ pregnant women currently recommend isoniazid preventive therapy.
A multicenter, double-blind, placebo-controlled, non-inferiority trial was conducted that randomly assigned 956 HIV+ pregnant women to receive the current standard of care of a 28-week course of IPT, which was initiated either during pregnancy (immediate) or 12 weeks postpartum (deferred). Mother-infant pairs were then followed for 4 years. This trial was conducted in countries with high burden of both HIV and TB: South Africa, Zimbabwe, Uganda, Botswana, Tanzania, Thailand, India, and Haiti.
Researchers found that 23.6% of women who received IPT during pregnancy experienced adverse pregnancy outcomes, versus 17% for those who received IPT at 12 weeks postpartum—a statistically significant difference. There were no significant differences in adverse outcomes among the live-born infants followed in the study.
Although isoniazid has been around since the 1950s, this is the first randomized trial to study isoniazid preventive therapy in pregnant women, and the first trial to compare safety in initiating IPT during pregnancy with deferring administration until postpartum. WHO’s clinical care guidelines are based on data from non-pregnant populations. Pregnant women have been excluded from clinical trials; thus the safety, efficacy, and optimal timing of IPT for pregnant women receiving antitretroviral therapy for HIV are unknown.
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Publication: National Institute of Allergy and Infectious Diseases
Study results published today help clarify how to safely prevent tuberculosis (TB) in women living with HIV who are pregnant or have recently given birth, are taking antiretroviral therapy, and live where TB is highly prevalent.
A clinical trial funded by the National Institutes of Health has found that for these women, treatment with the antibiotic isoniazid to prevent TB was similarly safe if begun during pregnancy or 12 weeks after delivery. However, there was significantly greater risk of poor health outcomes and death for the fetuses and newborns of these women if isoniazid preventive therapy began during pregnancy than if it began 12 weeks after delivery. This finding is concerning and merits research into alternative approaches to TB preventive therapy in pregnant women, according to the study investigators. Their findings are reported in the Oct. 3 issue of The New England Journal of Medicine.
“Pregnant women are often excluded from clinical research, which leads to an information gap that can pose a danger to maternal and infant health,” said Anthony S. Fauci, M.D. “The findings reported today give women, health-care providers and policy makers high-quality data for weighing the risks and benefits of TB preventive therapy for pregnant women living with HIV who are taking antiretroviral therapy.” Dr. Fauci is Director of the National Institute of Allergy and Infectious Diseases, a component of NIH that co-funded the trial.
TB is the top infectious-disease killer worldwide and the leading cause of death for people living with HIV. Among women, TB mainly affects those of reproductive age. When active TB disease develops during pregnancy or in the weeks after birth, it is associated with poor health outcomes for both the mother and baby. Access Full Article
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