Marissa Chmiola

Earlier this month, advocates from the Community Research Advisors Group (CRAG)—an international, community-based advisory body working to ensure the engagement of affected communities in tuberculosis (TB) research conducted by the Centers for Disease Control and Prevention (CDC) —published an article in The Lancet offering a community perspective on the use of the drug bedaquiline to treat drug-resistant and drug-susceptible TB. The US Food and Drug Administration (FDA) approved bedquiline for the treatment of drug-resistant tuberculosis—via an accelerated approval process—in December 2012, making it the first new drug from a novel class approved to treat TB in more than 40 years. Laia Ruiz Mingote and Dorothy Namutamba—co-chairs of CRAG— and Mike Watson Frick—TB/HIV Program Officer at GHTC member organization, Treatment Action Group—are among the article’s co-authors, and join us to answer questions about the article and discuss the benefits and risks of using bedaquiline to treat TB. Bedaquiline is the first new drug from a novel class approved to treat TB in more than 40 years. PATH/Katrina Peach Q: Bedaquiline has been shown to be effective in treating drug-resistant TB in combination with other drugs, but it also has some serious side-effects and risks. Explain what those are. In Phase II studies, bedaquiline showed promising activity against multidrug-resistant TB (MDR-TB). The drug reduced the average time to a negative TB culture from 18 to 12 weeks and increased the proportion of participants with a negative culture at 6 months from 58 percent to 79 percent. However, bedaquiline posed several safety concerns that should be addressed before testing the drug in people with drug-susceptible TB. Most attention has focused on bedaquiline’s association with QT prolongation—a potentially serious disturbance in the heart’s electrical rhythm. Other TB drugs also cause QT prolongation, including moxifloxacin and the other new MDR-TB drug, delamanid (developed by the company Ostuka). Other side effects of bedaquiline include liver toxicity, accumulation of phospholipids in cells, and even death. In one Phase II trial, a significantly higher number of participants receiving bedaquiline died than those receiving placebo. While these deaths did not have a common cause and occurred months after the trial, the FDA could not rule out the possibility that bedaquiline played a role. Since bedaquiline has a long half-life, meaning that it remains in the body for a long time, the drug may continue to pose a side effect risk to patients even after they stop taking it. Q: Given its side effects and risks, do you still believe bedaquiline merited accelerated approval by the FDA? Do you believe other countries should also approve bedaquiline’s use for drug-resistant TB? The accelerated approval was necessary. There are few effective treatment options for patients with MDR-TB and extensively drug-resistant TB (XDR-TB), and many of these patients are unable to tolerate existing options, as they also have strong side effects and risks of their own including hearing loss, neurological disturbances, and skin discoloration. However, there is a need for more information and clinical data to know how to manage the risks tied to bedaquiline. We have to make it clear that bedaquiline is not for all TB patients, but rather only for those people who are unable to tolerate other MDR-TB drugs to which their TB is susceptible or who might not survive without access to bedaquiline, as there are no other treatment options. In countries and regions with high incidence of drug-resistant TB, bedaquiline is a necessary and important addition to second- and third-line therapies. Yet most countries have been slow to approve bedaquiline, meaning that most patients can only access it through unreliable compassionate use mechanisms. Other countries, particularly those of the former Soviet Union, lack the legal frameworks that enable compassionate use. In countries with high incidence of drug-resistant TB, bedaquiline is an important addition to second- and third-line therapies. PATH/Nguyen Ba Quang Additionally, the high price of bedaquiline may discourage its use among patients who need it most. Janssen—the company that developed bedaquiline—has announced a tiered pricing scheme in which the price of bedaquiline varies depending on a country’s Gross National Income: high-income countries will pay about $30,000, middle-income countries will pay $3,600 and low-income countries will pay $900. Countries with the most severe MDR-TB epidemics are usually middle-income countries including South Africa, India, Russia, and China. While South Africa may be able to access the lowest price of bedaquiline, it’s unclear whether Janssen will extend the lower $900 price to other middle-income countries like China, where second-line TB drugs are not provided for free by the government. Can Chinese TB patients really afford bedaquiline at a price of $3,600? Even in high-income countries, the steep price of the drug can drain the general budget of TB programs, especially considering the high cost of other second-line drugs used to treat MDR-TB. Finally, in ensuring access to the treatment, Janssen must also make every effort to track safety and patient outcomes in people who receive bedaquiline. In the United States, a patient registry exists in theory, but many doctors do not know about the registry, and those who do have had difficulty enrolling patients into it. In the absence of a Phase III clinical trial of bedaquiline, patient registries may offer the best way to obtain additional safety data. Q: Clinical trial data on bedaquiline’s use for drug-resistant TB suggests it could also be effective in shortening treatment time for drug-susceptible TB as part of a first-line therapy combination. What are your concerns about the inclusion of bedaquiline in trials exploring its use for drug-susceptible TB? As mentioned, bedaquiline is a game changer in cases of MDR- and XDR-TB. However, for drug-susceptible TB, we have a well-established standard of care and other options for shortening treatment using existing drugs—such as rifapentine which is manufactured by Sanofi—or investigational drugs— such as PA-824 which was developed by the TB Alliance—that so far lack the safety signals observed in the Phase II trials of bedaquiline. The CDC’s Tuberculosis Trials Consortium will soon begin a Phase III study to see if replacing rifampicin with rifapentine can shorten drug-susceptible TB treatment from 6 to 4 months. The TB Alliance is also testing a 4-month drug-susceptible TB treatment regimen that uses a combination of PA-824, moxifloxacin, and pyrazinamide. Patients with drug-susceptible TB face a very different risk-benefit trade-off than people with drug-resistant TB. Currently, drug-susceptible TB has a safe and effective standard of care, although we agree that at six months, it is too long and there is the necessity to make it shorter. It is because of the safety of the regular regimen that, together with the current data, bedaquiline may not offer the best way forward for shortening drug-susceptible TB treatment. We believe that before studying bedaquiline for drug-susceptible TB, we need much more information about this new drug, its long-lasting presence in the body and common side effects. In addition, the use of bedaquiline in first line treatment could, in fact, risk an increase in resistance, leaving patients with fewer treatment options.

  Breastfeeding has served as the primary method for a mother to feed her infant since the dawn of humanity, but could it also be a way for her to administer life-saving medicines to her baby? The answer is yes—if a group of researchers from the United States and United Kingdom have their way. The JustMilk nipple shield contains a rapidly dispersible tablet containing drugs or nutrients that are delivered to the infant during breastfeeding. Photo: JustMilk The researchers—who have formed the nonprofit JustMilk—are developing a nipple shield device that allows a breastfeeding mother to administer drugs or nutrients to her infant through her breast milk. The device is easy to use—a mother would simply place the shield—which contains a rapidly dispersible tablet potentially containing antimalarials, antiretrovirals, antibiotics, or micronutrients—on her breast while feeding her child. As the milk passes through the device, it breaks down the tablet and delivers the medicines or nutrients to the infant. The “eureka moment” According to JustMilk’s cofounder Dr. Stephen Gerrard, PhD, the idea for the device emerged out of a design challenge—how to prevent HIV transmission during breastfeeding in developing countries—that his team was issued at the 2008 International Development Design Summit. The team had an idea to create a wearable device that deposits HIV-inactivating compounds into breast milk. After discovering the existence of both potential compounds and a wearable device—a nipple shield—the team realized it was on to something. “The eureka moment was that we could combine the two, and then you have a way of depositing antimicrobial compounds into milk,” said Gerrard. “The second point straight after that was—hang on—this could be a general drug and nutrient delivery device for infants.” Since then, the JustMilk team has focused on the broader potential of the device as a drug or nutrient delivery system. “Over 4.8 million infants under the age of one die each year from conditions like pneumonia, malaria, diarrhea, and HIV,” said Gerrard. “And an overwhelming majority of those conditions can be treated, and the deaths can be avoided by appropriate administration of agents to the infant….We’re trying to tackle those big issues, and we’re looking to make a major impact.” Overcoming the challenges of drug delivery in low-resource settings Gerrard believes JustMilk’s device offers advantages over conventional methods for administering drugs to infants, which often create challenges in low-resource settings. Liquid drug formulations can have a limited shelf life and require refrigeration; while powdered or dry formulations require reconstitution with potable water and can create accurate dosing issues. Gerrard believes a prefilled, disposable version of the JustMilk nipple shield could address many of these challenges, as well as empower a mother by allowing her to personally administrator medicine to her baby in a natural context. A work in progress: Putting users first JustMilk co-founders Geoff Galgon (left) and Dr. Stephen Gerrard, PhD (right) at the Saving Lives at Birth Challenge. Photo: JustMilk JustMilk, which received a grant last year from the Saving Lives at Birth Challenge, is still in the early stages of product development and is currently conducting research to inform the design, marketing, and eventual delivery of the device. In the next two months, JustMilk will begin user acceptability studies with mothers at the University of Venda in South Africa to answer questions like: should the device be disposable or prefilled with medicines, how should it be packaged, and would its use generate stigma for users—and if so—how can that be prevented? JustMilk also plans to conduct a study examining how infants react to intermittent use of the nipple shield to determine if the breastfeeding process is impacted by the infant using the shield once or twice a day. Gerrard sees that these studies are vital to the development process. “You have to have your end user right there from the beginning of the design process,” he said. “You have to get all these things right in the first place; otherwise, if you’re going through the clinical trial approval process and you’ve got something wrong, you’re going to have to go back again.” Gerrard acknowledges that the next six months will be a critical time period for the organization as it seeks to establish the viability of the product, mitigate any risks during its development, and potentially attract the involvement of medical device manufacturers. He explained, “Our goal with this device is to establish feasibility, demonstrate that it can confer a health benefit to infants, and hope the market reacts.” Marissa Chmiola is GHTC’s communications officer. JustMilk received a funding grant in 2013 from the Saving Lives at Birth Challenge—which is supported by the US Agency for International Development, the Bill & Melinda Gates Foundation, the Norwegian Ministry of Foreign Affairs, Grand Challenges Canada, and the UK Department for International Development. JustMilk has also received support from the Clinton Global Initiative, public health charity FHI 360, the University of Cambridge, and the National Collegiate Inventors and Innovators Alliance.

  Senate supports global health R&D in defense appropriations bill and report. Photo: Ken Kistler Earlier this month, we reported that both the House and Senate Appropriations Committees included language supporting global health research and development (R&D) in their reports concerning funding for the Department of State, foreign operations and related programs. Last week, we heard even more good news for global health R&D out of the Senate Appropriations Committee—this time related to the Department of Defense (DoD). The fiscal year (FY) 2015 defense appropriations bill—which was approved by the Committee last Thursday—includes a $7 million increase for peer-reviewed medical research—from $200 million in FY 2014 to $207 million this year—despite reducing overall DoD funding from FY 2014 levels. In addition, in the accompanying report, the Appropriations Committee includes very strong language recognizing DoD’s substantial contributions to global health R&D and the need to support sustained US investments in this area. The committee report includes language submitted by GHTC recognizing “the critical contribution that the department’s [R&D] portfolio makes in protecting our troops from infectious and neglected diseases they may encounter on missions around the world” and noting “the need to sustain and support US investment in this area by fully funding those R&D programs that carry out this work.” Committee recognizes role of infectious disease research in improving US security The committee report also recognizes the threat that neglected infectious diseases—such as malaria, dengue fever, and Chikungunya—pose to the effectiveness of US forces deployed overseas and expresses concern over reductions in research funding for these disease areas. In the report, the committee notes that it is “concerned with the department’s decisions over recent years to precipitously decrease funding for malaria research” and that it “encourages the department to address diseases of military importance and invest in research for chemoprophylaxis, surveillance, and other countermeasures.” Photo: PATH/Gabe Bienczycki Report calls for DoD to improve coordination across R&D programming The committee report also includes language—submitted by GHTC—which directs each DoD program involved in infectious disease research to submit a report of its R&D activities to the House and Senate Defense Committees outlining the program’s funding and accomplishments from FY 2011 through 2014. As well, the committee urges DoD to partner with other organizations involved in infectious diseases research—including other federal agencies—to mitigate the duplication of research efforts and maximize the use of DoD resources. It is GHTC’s hope that these reports and activities will lead to improved coordination across DoD global health R&D programs, as well as improved coordination across all US agencies involved in global health R&D, which will in turn help fill current gaps in research programming and assure US investments are used most effectively. GHTC is glad to see the Senate recognizing DoD’s critical role in global health R&D, as well as advocating for sustained funding and improved coordination for global health R&D programming at DoD. We are hopeful that the language included in the Senate defense appropriations report will be included in whatever final legislation is passed.

During the past year, leaders from the US Global Leadership Coalition (USGLC)—an advocacy organization promoting diplomacy and development—have traveled across America seeking out innovators and innovations that best demonstrate how strategic US investments in global development can enhance America’s foreign policy and security interests—an approach USGLC calls “smart power” diplomacy. The VVM is a health innovation that is saving lives and money. Photo: Umit Kartoglu Not surprisingly, USGLC leaders discovered that investments in global health innovation are an essential part of America’s “smart power” toolbox. As USGLC leaders traveled from city to city, they discovered numerous examples of how American businesses and nongovernmental organizations (NGOs) are working with the US government to deliver global health innovations that are not only improving lives worldwide, but also creating jobs here in the United States and enhancing America’s global leadership. In fact, nearly half of the 30 programs USGLC identified as “leading American innovators” in its Innovations in Smart Power report—released today—focused on improving global health and nutrition. The report featured two innovations developed by GHTC members, including the PATH-developed Vaccine Vial Monitor (VVM), which indicates whether vaccines have been damaged from exposure to heat. The VVM not only saves lives, but also produces an estimated $14 million annual savings by preventing undamaged vaccines from being discarded. USGLC also featured the Global Health Fellows Program II—led by the Public Health Institute—which brings private sector experts from America to low- and middle-income countries in Africa and Asia—for up to three months—to share their expertise in research and medical technologies with healthcare workers in local communities. Two interns sponsored by the Global Health Fellow Program help build a house for an HIV expectant mother in Uganda. Photo: Global Health Fellows Program II/PHI Other creative global health innovations featured in the report include low-cost toilets to reduce diarrheal disease, fortified peanut paste to combat malnutrition, and an easy squeeze pouch to help HIV-positive mothers deliver antiretroviral drugs to their newborn babies. All of these projects were supported by the US government, and demonstrate how American ingenuity and investments can tackle some of the world’s greatest global health problems. It’s clear that sustained American investment in global health innovation not only supports domestic and international health improvements and economic growth, but also serves as an important diplomatic tool and a demonstration of America’s character. In other worlds, investing in global health innovation=smart power.

Tomorrow US policymakers and global health advocates will come together to talk progress made on preventing maternal and child deaths. During the day, the US Agency for International Development (USAID) will host a high-level forum called Acting on the Call: Ending Preventable Child and Maternal Deaths to both celebrate progress and assess the challenges that remain. That evening, the 5th Birthday and Beyond coalition will celebrate America’s leadership and investments worldwide to help children reach their fifth birthday. US investment in R&D has led to new innovations that are saving the lives of mothers and children. Photo: PATH/Teresa Guillien While you’ll probably hear a lot of different facts and figures, one message will be clear—the world has made remarkable progress in preventing the deaths of millions of women and children. In fact, maternal and child deaths have been cut in half in just over two decades. That means that every day this year, 17,000 more children will live and 700 more mothers will survive childbirth than did two decades ago. Central to this progress has been US investment in research and development (R&D) that has led to new medicines and innovative health products that are saving the lives of mothers and children. Globally new vaccines, drugs, diagnostics, and other health innovations have led to 4.2 million fewer child deaths in 2013 compared to 1990, according to a report by the Institute for Health Metrics and Evaluation. Innovations like the polio vaccine, oral rehydration solution to treat diarrhea, and antiretroviral therapies that prevent maternal to child HIV transfer, and others treatments have resulted in incredible gains for maternal and child health.   No country has done more than the United States to help save the lives of the world’s poorest mothers and children. A critical part of the US approach has been our world-leading investment in global health R&D. In fact, the US government is the largest funder of global heath R&D in the world—contributing over 45 percent of total investment. US government investment in global health R&D has led to breakthroughs that have transformed or are poised to transform efforts to reduce maternal and child mortality. Some examples include: The Oxytocin-Uniject™ This is a device filled with oxytocin that helps contract the uterus to reduce post-partum hemorrhage—or excessive bleeding—the leading cause of maternal death worldwide. It is easy to inject and requires little training to administer, so it’s made a dramatic difference in the ability of health workers to administer oxytocin in emergencies or in remote locations outside of traditional hospital facilities. USAID played a crucial role in funding research towards the development of this product. RTS,S malaria vaccine candidate RTS,S is the most clinically-advanced vaccine candidate for malaria—a disease which kills a child every 40 seconds. A recent study showed that infants who receive the RTS, S vaccine had one third fewer cases of both clinical and severe malaria. A vaccine could be an important tool in reducing child sickness and death from malaria. The Department of Defense provided critical funding for the early development and clinical testing of RTS,S. Rotavirus vaccines Rotavirus-induced diarrheal disease kills roughly 435,000 children younger than five each year. Two currently available rotavirus vaccines were introduced in the past two decades, with other vaccines under development showing tremendous progress. The National Institutes of Health developed the first available rotavirus vaccine and has been a financial partner in the development of subsequent vaccines. In addition, the Centers for Disease Control and Prevention also monitors efficacy and safety, and supports clinical trials of rotavirus vaccines. New contraceptive technologies Family planning technologies allow women to space their pregnancies—making it more likely for both the mother and child to survive childbirth. An analysis of 172 countries found that family planning prevented 272,000 maternal deaths in just one year. However, the contraceptive options that exist today don’t always meet the needs of women in developing countries. New vaginal rings are being developed that will be long-lasting and easy for the user to insert and remove without a doctor’s assistance, while new multipurpose prevention technologies combine the delivery of contraceptives with microbicides which reduce the transmission of HIV and other sexually transmitted infections. USAID provides funding towards the development of many of these new contraceptive technologies. While tremendous progress has been made in decreasing maternal and child deaths worldwide thanks in part to new health innovations, each year 6.6 million children still die before their first birthday and 289,000 women still die from pregnancy-related causes. That translates to 18,000 children under the age of five and 800 pregnant women or women in childbirth dying every single day. The United States can and must do more. While the United States should increase access to proven and existing drugs, vaccines, and other health tools for maternal and child health, it is just as critical to develop the next generation of tools to prevent and treat existing and emerging diseases. Sustained and continued investment by the US government in global health R&D is critical to ending maternal and child deaths.

The answer is yes according to a group of 35 leading scientists who have come together to explore new strategies to accelerate vaccine development for deadly diseases such as malaria, HIV, tuberculosis (TB), and cancer. These scientists—who are part of planning a new initiative called the Human Vaccines Project (HVP)—hope that just as the Human Genome Project successfully mapped the building blocks of human life and led to numerous drug development and medical breakthroughs, a Human Vaccines Project could decipher the “human immunome”—providing a road map of the human immune system that would help scientists accelerate the development of vaccines for existing and emerging diseases. On Wednesday, Nature Immunology released a paper by researchers exploring the HVP that outlined the challenges to vaccine development, the opportunities presented by recent technological advances, and a broad vision for HVP’s future work. Could mapping the “human immunome” lead to the next generation of vaccines? Scientists hope yes. Photo: PATH/Aaron Joel Santos “A Human Vaccines Project focused on solving the major scientific problems impeding vaccine development could be transformative for efforts to help prevent these devastating infectious diseases as well as certain cancers,” said Wayne C. Koff, Chief Scientific Officer of the International AIDS Vaccine Initiative (IAVI) and lead author of the report. Vaccines are among the most effective interventions in the history of public health, having led to the eradication or near eradication of diseases like smallpox and polio and the collective prevention of 2-3 million deaths per year. However, scientists have not yet been able to develop broadly effective vaccines against a number of common and deadly diseases like malaria, AIDS, TB and cancer.   Why do vaccines for some diseases elude us? One of the reasons is because the viruses that cause these diseases are so complex and clever. Take for example variable viruses like influenza and HIV. These viruses behave sort of like characters from the Transformer movie. Like Optimus Prime, they constantly mutate, evolve, and change their form—making it difficult for scientists to develop a vaccine against them. Other viruses are just tough nuts for scientists to crack. For example, the respiratory syncytial virus (RSV)—which causes respiratory infection in infants—has mechanisms that not only block the immune system’s ability to signal to certain cells that it has been compromised, but also alters the immune system’s “memory” processes which typically allows it to react more quickly to subsequent exposure to the same pathogen. As a result, RSV re-infects people throughout their lives. Another challenge impeding vaccine development is the fact that different individuals’ immune systems respond differently to the same virus. In particular, the immune systems of infants and the elderly behave differently than those of adults, so a vaccine that works for adults may not work for either of these populations. In addition, our immune system can react haphazardly when it is assaulted from multiple fronts. For example, rotavirus vaccines are more effective in the developed world than in developing countries where people’s immune systems—as a result of poor sanitation, water and hygiene—are often already fighting off other infections. The opportunity and vision for a Human Vaccines Project Despite these challenges, the paper notes that scientific and technological breakthroughs over the last decade have introduced news tools and technologies that provide an opportunity to revolutionize vaccine development. An HVP would hope to exploit these technologies to change how vaccine development is undertaken. Drawing a parallel to the success of the Human Genome Project, HVP envisions a large-scale, highly collaborative effort—estimated at $1 billion over the next decade—that would bring together industry, government, academia, and nongovernmental organizations to work together to tackle the challenges outlined above. Part of the project’s approach will be a major effort to map the “human immunome.” What does it mean to map the “human immunome”? The human immune system is a series of cells with receptors that recognize and respond to the introduction of foreign substances into the body. It’s a complicated system with an enormous diversity of cells working together to weed out and attack viruses and infections. Traditionally vaccine research has focused more on results coming from experimentation for a specific disease, rather than on understanding the underlying principles of the immune system. Relatively little is known about the interaction of immune responses and cellular processes that provide immunity in response to a vaccination. In the past it would have been inconceivable to try to map the immune system because of the sheer number of genetically different cells involved, but due to improvements in genetic sequencing technologies and computer tools to manage and analyze large data sets, the paper’s authors now believe it could be possible to figure out the sequence of all those receptor cells in the human adaptive immune system. Like the Human Genome Project, such an initiative could take many years, but it would create an essential public tool with the potential to transform the science of vaccine development.