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
With the highest burden of tuberculosis and drug-resistant TB globally, treatment success rate of less than 50%, and alarming rates of loss to follow-up and mortality, India faces serious challenges in the fight against TB. Preventing the spread of disease is critical. Proximity places household contacts of TB patients at particularly high risk of infection.
The Indo-JHU Clinical Research Team is invested in preventing household spread of TB. From 2015–2017, the site participated in a multinational, cross-sectional feasibility study to assess whether it was possible to reach adult and child household members of MDR-TB patients, evaluate their baseline health, determine HIV status (a known risk factor for TB), and assess their knowledge, attitudes, and perceptions about TB disease, preventive therapy, and participating in research. What the study team found was that household contacts of MDR-TB patients were eager for information about, and therapy for, preventing TB infection.
Following the feasibility study, the BJGMC-CRS now is poised to begin the PHOENIx Phase III clinical trial on protecting household contacts of newly diagnosed MDR-TB index cases. The trial is being conducted under two trial networks: the AIDS Clinical Trials Group (ACTG) and the International Maternal, Pediatric, Adolescent, AIDS Clinical Trials Network (IMPAACT), and is sponsored by the U.S. National Institutes of Health. The multicenter trial will be conducted in Haiti, South Africa, Uganda, and India and will assess efficacy and safety of two anti-TB medicines: isoniazid and delaminid.
Collaboration and coordination with local government TB program officials are critical for ensuring transparency and a shared understanding of the study’s purpose, methods, consent process, logistics, and potential implications for India’s national TB control efforts. To that end, the Research Team recently convened the first PHOENIx study community sensitization workshop for supervisors of Maharashtra’s state government TB control program. Fifty-four participants were in attendance, including Dr. Padmja Jogewar, the supervising TB officer for the state; Dr. Sanjay Darade, the supervising TB office for the district of Pune; the medical officer from the state TB demonstration and training centre as well as medical officers, MDR-TB supervisors, and state TB supervisors. Representation from BJGMC included Dean Dr. Sudhir Nanandkar, Deputy Dean Dr. Samir Joshi, PHOENIx study lead and Head of TB Department Dr. Sanjay Gaikwad, and the BJGMC outreach team. Dr. Vidya Mave, Indo-JHU Clinical Research Site Director, welcomed the audience and introduced guest speakers. Dr. Jogewar spoke of the need for research on preventive therapy for MDR-TB, and she offered the full support from the Revised National Tuberculosis Control Program (RNTCP) in Marharashtra state. BJGMC Dean Dr. Nanandkar expressed the importance of the study and pledged institutional support. Dr. Nishi Suryavanshi, Deputy Director of the Indo-JHU Clinical Research Partnership presented an overview and background of the study, and Dr. Sandesh Patil explained the study schema, eligibility criteria for participant enrollment, and procedures. Community Outreach Coordinator Ms. Savita Kanade discussed logistics for participant involvement.
The team is eager to begin, and grateful for the support of local collaborators who are dedicated to control of TB in India.
February 8, 2019—PUNE—Staff and nearly 140 participants in the REPRIEVE study gathered on February 8, 2019, at the BJGMC Clinical Trial Site for an awareness event and luncheon promoting healthy behaviors and engagement in care. The gathering featured banners on maintaining health as well as information about tobacco and alcohol use, messaging about exercise and a balanced diet, uplifting musical performances, and an energetic and very well-received open microphone forum for participants to share their experiences and perspectives if they wished. REPRIEVE is a multi-center, multi-network, randomized, double blind, placebo controlled, AIDS Clinical Trial Network (ACTG) trial addressing whether taking a daily statin drug can help prevent major adverse cardiovascular events in people living with HIV who are over age 40, have a CD4 count higher than 100, have received ART for more than 6 months, and had a variable Atherosclerotic Cardiovascular Disease (ASCVD) risk score at enrollment. All three sites of the BWI-CTU consortium—Johns Hopkins University in Baltimore, Maryland; BJGMC in Pune, India; and Whitman-Walker-Health in Washington, DC—are enrolling participants in the trial. The BJGMC Clinical Research Site recruited 250 participants between August 2017 and January 2019, who will be followed for 96 months. More information about the study can be found on the REPRIEVE Trial website: http://www.reprievetrial.org Participant retention can be real challenge in clinical trials, particularly in India where there are many barriers to maintaining care and considerable stigma associated with disease. So events such as this are important in helping to build a community focused on a shared health issue and in keeping people engaged in that community. Engaged participants are more knowledgeable about health and strategies to maintain it, are more likely to stay connected to the care they need, and often serve as health ambassadors in their communities. The event was coordinated and convened by Clinical Coordinator Dr. Sandesh Patil and the REPRIEVE Study Team. Speakers included leadership from the Clinical Research Site, Drs. Vidya Mave, Nishi Suryavanshi, and Nikhil Gupte as well as Site PI Dr. Shashikala Sangle. CCGHE’s Director Dr. Robert Bollinger and Deputy Director Dr. Amita Gupta also delivered remarks thanking participants for their contributions and study team members for their work on behalf of HIV patients, and acknowledging the enduring and effective research partnership between Johns Hopkins and BJGMC. The most powerful part of the event was hearing from participants, who were enthusiastic and eager to share their perspectives about research and the REPRIEVE Team. Their stories were personal and heartfelt. One person viewed participation as a public service: “Being HIV infected, we cannot donate blood or any organ, however we can participate in clinical trials that address important public health concerns [for the] betterment of society and mankind.” Another participant explained how inclusion in the study offered rapid access to urgent lifesaving care: “. . . I had severe abdominal pain. I am thankful to the study team for prompt assistance in investigations, diagnosis and the swift surgery. I am here today only because of the study team.” One woman shared a particularly inspiring reflection on her decades-long journey with HIV: “I came know about my HIV-infected status when I was pregnant 20 years back. Today my son is graduating as an engineer. I am taking my medicines regularly. The study staff take very good care of us.” The ultimate goal of research is to improve patient health, but often what’s lost in aggregated clinical data is the tremendous personal impact that study participation has for patients and their families. Gatherings among team members and participants help foster community and a shared mission to improve disease prevention, diagnosis, and treatment.
The Indo-JHU Clinical Research partnership at Byramjee Jeejeebhoy Government Medical College (BJGMC) in Pune, India, is on an enrollment roll. The team has enrolled more than 6,000 participants in clinical trials and epidemiological studies, with approximately 1,200 during the last year. Indo-JHU research is led by Dr. Vidya Mave, Dr. Nishi Suryavanshi, and Dr. Nikhil Gupte in collaboration with BJGMC Deans Ajay Chandanwale and Sameer Joshi, and several heads of department, including Drs. Sangle of Medicine, Bhosale of Obstetrics and Gynecology, Bharadwaj of Microbiology, Kinikar of Pediatrics, and Gaikwad of Chest Medicine.
According to BJGMC Clinical Research Site (CRS) Director Dr. Vidya Mave, “The growth in the numbers of studies and participants has presented challenges that the team has really risen to. Among contributions of more than dedicated 150 team members, we owe much of our participant recruitment and management success to effective community outreach led by Savita Kanade and truly impressive coordination of studies by Dr. Nishi Suryavanshi. The CRS team is making a difference, and we take pride in our site’s contributions.”
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Isoniazid preventive therapy (IPT) during and after pregnancy in women living with HIV on antiretroviral therapy (ART) in tuberculosis (TB) endemic areas in Africa, Asia and Haiti resulted in serious adverse events quite possibly attributable to isoniazid with no significant reduction in TB cases, participants heard last week at the Conference on Retroviruses and Opportunistic Infections (CROI 2018) in Boston.
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