NIH researchers identify how two people controlled HIV after stopping treatment

Research led by scientists at the National Institutes of Health has identified two distinct ways that people with HIV can control the virus for an extended period after stopping antiretroviral therapy (ART) under medical supervision. This information could inform efforts to develop new tools to help people with HIV put the virus into remission without taking lifelong medication, which can have long-term side-effects.

The study, published today in the journal Nature Medicine, was led by Tae-Wook Chun, Ph.D., chief of the HIV Immunovirology Section in the Laboratory of Immunoregulation at the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH; and by Anthony S. Fauci, M.D., NIAID director and chief of the Laboratory of Immunoregulation.

The study involved two adults with HIV who began ART soon after acquiring the virus and continued with treatment for more than six years, successfully suppressing HIV. The individuals then joined an HIV clinical trial and stopped taking ART under medical supervision. The study team followed one of these people for four years and the other for more than five years, with study visits roughly every two to three weeks.

The investigators monitored the timing and size of viral rebounds in each participant, that is, times when the amount of HIV in their blood became detectable. One participant suppressed the virus with intermittent rebounds for nearly 3.5 years, at which point he began taking suboptimal ART without telling the study team. The other participant almost completely suppressed HIV for nearly four years, at which point the virus rebounded dramatically because he became infected with a different HIV strain, a phenomenon known as “superinfection.”

In the first participant but not the second, the scientists found high levels of HIV-specific immune cells called CD8+ T cells that can kill virus-infected cells, indicating that different mechanisms of control were at work in each person. The researchers also found that the second participant, who had a weaker CD8+ T cell response against HIV, had a very strong neutralizing antibody response throughout the follow-up period until the sudden viral rebound. According to the scientists, this suggests that neutralizing antibodies may have played a significant role in facilitating near-complete HIV suppression in this individual until he newly acquired a different strain of the virus.

The researchers emphasized that to avoid the emergence of viral resistance and prevent potential misinterpretation of scientific data in studies like this one, it is important to conduct routine antiretroviral drug testing of people with HIV who halt treatment for extended periods. In addition, the researchers identified HIV superinfection as a potential cause of sudden virologic breakthrough in people with HIV who halt treatment, especially when the breakthrough occurs after a prolonged period of virus suppression.

Article

J et al. Distinct mechanisms of long-term virologic control in two HIV-infected individuals after treatment interruption of antiretroviral therapy. Nature Medicine DOI: 10.1038/s41591-021-01503-6 (2021).

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New model sheds light on evolution of Earth’s oxygen

Ateam led by Southwest Research Institute has updated its asteroid bombardment model of the Earth with the latest geologic evidence of ancient, large collisions. These models have been used to understand how impacts may have affected oxygen levels in the Earth’s atmosphere in the Archean eon, 2.5 to 4 billion years ago.

When large asteroids or comets struck early Earth, the energy released melted and vaporized rocky materials in the Earth’s crust. The small droplets of molten rock in the impact plume would condense, solidify and fall back to Earth, creating round, globally distributed sand-size particles. Known as impact spherules, these glassy particles populated multiple thin, discrete layers in the Earth’s crust, ranging in age from about 2.4 to 3.5 billion years old. These Archean spherule layers are markers of ancient collisions. “In recent years, a number of new spherule layers have been identified in drill cores and outcrops, increasing the total number of known impact events during the early Earth,” said Dr. Nadja Drabon, a professor at Harvard University and a co-author of the paper.

“Current bombardment models underestimate the number of late Archean spherule layers, suggesting that the impactor flux at that time was up to 10 times higher than previously thought,” said SwRI’s Dr. Simone Marchi, lead author of a paper about this research in Nature Geoscience. “What’s more, we find that the cumulative impactor mass delivered to the early Earth was an important ‘sink’ of oxygen, suggesting that early bombardment could have delayed oxidation of Earth’s atmosphere.”

The abundance of oxygen in Earth’s atmosphere is due to a balance of production and removal processes. These new findings correspond to the geological record, which shows that oxygen levels in the atmosphere varied but stayed relatively low in the early Archean eon. Impacts by bodies larger than six miles (10 km) in diameter may have contributed to its scarcity, as limited oxygen present in the atmosphere of early Earth would have been chemically consumed by impact vapors, further reducing its abundance in the atmosphere.

“Late Archean bombardment by objects over six miles in diameter would have produced enough reactive gases to completely consume low levels of atmospheric oxygen,” said Dr. Laura Schaefer, a professor at Stanford University and a co-author of the paper. “This pattern was consistent with evidence for so-called ‘whiffs’ of oxygen, relatively steep but transient increases in atmospheric oxygen that occurred around 2.5 billion years ago. We think that the whiffs were broken up by impacts that removed the oxygen from the atmosphere. This is consistent with large impacts recorded by spherule layers in Australia’s Bee Gorge and Dales Gorge.”

SwRI’s results indicate that the Earth was subject to substantial numbers of large impacts throughout the late Archean era. Around 2.4 billion years ago, during the tail end of this bombardment, the Earth went through a major shift in surface chemistry triggered by the rise of atmospheric oxygen, dubbed the Great Oxidation Event (GOE), which is attributed to changes in the oxygen production-sink balance. Among the proposed scenarios are a presumed increase in oxygen production and decrease in gases capable of removing oxygen, either from volcanic sources or through their gradual loss to space.

“Impact vapors caused episodic low oxygen levels for large spans of time preceding the GOE,” Marchi said. “As time went on, collisions become progressively less frequent and too small to be able to significantly alter post-GOE oxygen levels. The Earth was on its course to become the current planet.”

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Mars: Jezero crater really was a lake

The first published data from the Perseverance rover shows that there was a large, deep lake on Mars 3.6 billion years ago, and that it was swept away by a climate upheaval.

After years of preparation and the nerve-wracking take-off and landing phases, the publication of the very first results of a space mission is always a very special moment. Those of Perseverance, published today in the journal Science,1 are no exception: as we suspected, Jezero crater, the site 35 kilometers in diameter where the rover landed in February 2021, welcomed a real lake several billion years ago.

Finding traces of water and selecting samples

Confirming this hypothesis requires images of vertical surfaces such as cliffs, something that cannot be obtained using orbital observations, however invaluable they may be. Only a rover with on-board cameras can study them directly. NASA’s Mars 2020 mission, supported by an international team, initially set two major objectives for Perseverance.

“The mission’s goal is to use the rover to help us understand the geology and ancient climate of Mars, and to try to detect traces of past life which might still be preserved,” explains Nicolas Mangold, CNRS senior researcher at LPG.2 “To do this, Perseverance has to sample rocks of various types and ages.” The rover is therefore focusing on sedimentary rocks formed in the presence (or not) of water and on older samples of crust, such as those found in the Gale crater, currently being explored by the Curiosity rover.

Perseverance will also have to select some forty samples, which will be the first ever brought back to Earth. This unprecedented return will be carried out by two other US / European collaborative missions, still under development and planned for the early 2030s.

A lake fed by a river

In the meantime, Perseverance is hard at work. Its first scientific results have just been published in the prestigious journal Science, with Mangold as lead author.3 The findings first of all confirm that, around 3.6 billion years ago, the Jezero crater really was a lake fed by a river flowing through a delta. The circular body of water covered an area 35 kilometres in diameter and was several tens of metres deep.

SuperCam superstar

These discoveries were only made possible by studying sedimentary strata on Kodiak Butte, located in the former delta. But although Perseverance landed two kilometres from its initial target, its seven on-board instruments still enabled it to operate remotely. SuperCam, its main instrument, is an impressive camera whose job is to observe and analyse rocks. It is operational even when analysing objects around ten centimetres in size located several kilometres from the rover.

“SuperCam is unusual in that it brings together five different techniques,” explains Sylvestre Maurice, a researcher at IRAP4 and co-Principal Investigator for the camera. “One instrument provides information about the elemental chemical composition of the rocks, two others analyse their mineralogy, a camera takes high-quality remote images and, last but not least, a microphone succeeded in making the first recording of sounds on Mars. We had to juggle the requirements of each component to make them fit into a single instrument that is as innovative as it is complex.”

A rover with 20 cameras

Although SuperCam only provides a very narrow field of view, Perseverance is armed with twenty or so cameras altogether, including Mastcam-Z, which also helped to obtain these first results. All this material has to survive the launch, the journey to Mars, the landing and the conditions on the planet, where the day / night cycles are accompanied by abrupt changes in temperature. The French teams were able to rely on their expertise since they had previously developed a similar although simpler instrument, ChemCam, used on the Curiosity rover, which has now been on Mars for nine years.

In France, around 300 people worked on SuperCam under the supervision of the French space agency CNES.5 “We are continuing France’s strong commitment to Mars surface missions,” Maurice says. “The French scientific community is heavily involved in the Insight mission, for which it provided the seismometer, and in the European ExoMars mission, scheduled for launch in September 2022.”

Objective delta

“Of course, it’s reassuring that we have already found what we were looking for, but this kind of result always raises more questions than it answers,” Mangold points out. “On the basis of these findings, we plan to take Perseverance across the former delta to undertake a detailed analysis of the strata observed, and in particular of the fluvial sediments located at the top, to try to understand the origin of the climate transition and analyse the large boulders that were probably transported from the ancient crust.”

The teams will therefore have to determine a route that will let the rover access all the geological layers in the Jezero crater. This may then reveal the environment in which water entered the delta before flowing into the lake. But for now, Perseverance can take a break. As happens every two years, Mars is on the opposite side of the Sun from the Earth, cutting off all communication for three weeks.

Footnotes

• 1.N. Mangold et al., “Perseverance rover reveals ancient delta-lake system and flood deposits at Jezero crater, Mars”, Science, 7 October 2021. DOI : 10.1126/science.abl4051
• 2.Laboratoire de planétologie et géodynamique (CNRS/Université de Nantes/Université d’Angers).
• 3.In addition to the LPG, the CNRS researchers involved in this work are from the Institute for Research in Astrophysics and Planetology (IRAP, CNRS / CNES / UT3 Paul Sabatier), the Lyon Geology Laboratory: Earth, Planets, Environment (LGL-TPE, CNRS / ENS Lyon / Université Claude Bernard Lyon 1) and the Institute of Mineralogy, Materials Physics and Cosmochemistry (IMPMC, CNRS / MNHN / Sorbonne University).
• 4.Institute for Research in Astrophysics and Planetology (CNRS / Toulouse Paul Sabatier University / French National Centre for Space Studies).
• 5.French National Centre for Space Studies.

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Breath test can identify COVID-19 in critically ill patients

Instead of an invasive nasal swab, researchers at The Ohio State University Wexner Medical Center are exploring the use of a unique breath test for the rapid screening of patients for COVID-19.

Results from the initial study in patients, published today in the journal PLOS ONE, found the breath test is highly accurate in identifying COVID-19 infections in critically ill patients.

“The gold standard for diagnosis of COVID-19 is a PCR test that requires an uncomfortable nasal swab and time in a lab to process the sample and obtain the results,” said Dr. Matthew Exline, lead researcher, director of critical care at University Hospital and professor of internal medicine at Ohio State. “The breathalyzer test used in our study can detect COVID-19 within seconds.”

COVID-19 infection produces a distinct breath print from the interaction of oxygen, nitric oxide and ammonia in the body. The breath detector device, developed by Pelagia-Irene Gouma, researcher and professor in Ohio State’s departments of Materials Science and Engineering and Mechanical and Aerospace Engineering, and Milutin Stanaćević, associate professor in the Department of Electrical and Computer Engineering at Stony Brook University, can detect the breath print of COVID-19 in exhaled breath within 15 seconds.

“This novel breathalyzer technology uses nanosensors to identify and measure specific biomarkers in the breath,” said Gouma. “This is the first study to demonstrate the use of a nanosensor breathalyzer system to detect a viral infection from exhaled breath prints.”

The study followed 46 patients in the intensive care unit with acute respiratory failure that required mechanical ventilation. Half of the patients had an active COVID-19 infection and the remaining half didn’t have COVID-19. All patients had a PCR COVID-19 test when they were admitted to the unit.

Researchers collected exhaled breath bags from the patients on day 1, 3, 7 and 10 of their inpatient stay. The breath bag samples were tested within four hours of sample collection in a lab. The breath print was identified in patients with COVID-19 pneumonia with 88% accuracy upon admission to the ICU.

“PCR tests often miss early COVID-19 infections and results can be positive after the infection has resolved,” Exline said. “However, this noninvasive breath test technology can pick up early COVID-19 infection within 72 hours of the onset of respiratory failure, allowing us to rapidly screen patients in a single step and exclude those without COVID-19 on mechanical ventilation.”

The use of breathalyzer technology to rapidly diagnose patients with respiratory infections has the potential to greatly improve the ability to rapidly screen both patients and asymptomatic people. Future studies will look at the use of this technology for less severe COVID-19 patients and will explore whether other diseases and infections could benefit from it.

The research team has applied to the U.S. Food and Drug Administration for emergency use authorization of the breathalyzer technology.

Andrew S. Bowman, associate professor of veterinary preventive medicine at Ohio State, contributed to this study.

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Medical research reduces deaths in areas where it is created

A new study provides a novel way of showing that medical research does indeed save lives, starting in the local communities where it is produced.

Researchers analyzed whether publication of scientific studies related to specific diseases reduced mortality rates for each disease in regions in which the research took place.

These studies might describe new treatments or other ways of managing diseases that could benefit patients and add years to their lives.

The results showed that a 1% increase in publications on a specific disease produced by local researchers reduces the mortality rate for that disease in the area by 0.35%. That reduction occurred in the first five years following the publication of the research.

“The idea is that physicians who are in the same geographical area as the developers of a new medical idea are more likely to be early adopters of that idea,” said study co-author Rebecca McKibbin, who is a lecturer at the University of Sydney in Australia.

“Our findings provide a way to measure how much biomedical research directly impacts life expectancy.”

McKibbin, who began the work while visiting The Ohio State University, conducted the study with Bruce Weinberg, professor of economics at Ohio State. Their study appears as a working paper at the National Bureau of Economic Research and has not yet been peer reviewed.

Beyond finding a link between medical publications and lowered mortality, the researchers found that the link between health and research went further upstream to funding, with an increase in funding of medical research linked to fewer deaths in the region.

In that case, a 1% increase in local funding for research on a particular disease reduced local mortality from that disease by 0.22%.

Funding of scientific studies had significant links to lower mortality that appear to run through publications, Weinberg said.

“This is not a small rate of return,” Weinberg said. “The results provide additional evidence that funding medical research is a good investment.”

The study looked at mortality rates from 1999 to 2017 for 38 diseases, 19 of which were cancers. Researchers measured age-adjusted years of potential life lost, which places greater weight on deaths at younger ages relative to older ages.

Mortality rates were measured for each hospital referral region in the United States – basically, areas served by the same major hospitals.

The number of research publications came from the PubMed database, which is an index of more than 32 million biomedical research publications.

The question was whether more studies on a particular disease coming out of universities and other research centers in a particular area helped reduce deaths by that disease in the local community – and the answer was yes.

“Physicians and other health care providers hear about the idea first through local networks, which means they put the ideas into practice sooner. That gives a health advantage to people with that disease in locations where research is conducted,” McKibbin said.

To establish a causal link between research and health, the researchers looked at changes in funding of biomedical research to measure the impact of new findings on mortality rates. Here they looked at grants from the National Institutes of Health to researchers investigating specific diseases. The NIH invests about $41.7 billion each year in medical research.

Here again, grants to researchers in a specific community helped reduce mortality in that area in the following years for diseases that they were studying.

Finally, the researchers looked at a single sharp “shock” to medical research funding that occurred with the American Recovery and Reinvestment Act (ARRA), signed into law in 2009. The ARRA increased the NIH budget by $8 billion in 2009 and 2010.

The study examined what happened to life expectancies for people with specific diseases in communities that received additional funding from ARRA.

“This funding represents an unexpected windfall to the area to study a particular disease,” Weinberg said. “We found that it also was linked to reduced mortality in the diseases it targeted.”

For the study, the researchers took into account a variety of other factors that may also affect mortality. For example, they controlled for mortality trends for each area, in case deaths were increasing in one area more than others. They also controlled for mortality trends by disease, in case some diseases are becoming worse over time. And they controlled across areas for the diseases that are causing local deaths, in case some diseases are more prevalent in certain communities due to environmental or other factors.

Even after taking these factors into account, medical research helped patients live longer.

McKibbin said this study took a more direct way of measuring research impact than many other studies.

Most studies have focused on how medical research affects factors like patents or new medicines to treat diseases, McKibbin said.

“Here we identified the impact of biomedical research on health itself, as opposed to the intermediate steps such as the development of new pharmaceutical products,” Weinberg said.

The findings also show the importance of sharing research findings, according to Weinberg.

“In addition to translating basic science into treatments, there should be a focus on disseminating valuable research findings to the health care professionals who can put them into practice. Our findings suggest that mortality may decline when that happens.”

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Nature and climate crises: two sides of the same coin

A changing climate means changing habitats. This in turn further intensifies the effects of climate change, which cause biodiversity loss. To stop this cycle, researchers are looking towards nature-based solutions.

Biodiversity, the unique variety of life on our planet, is more than just flora and fauna. It’s the lynchpin to the continued existence of our species. Remove the pin, and everything begins to come apart – climate, food chains, weather, the economy, our way of life and place in the natural world.

Yet the degradation of Earth’s biodiversity is caused by human activities: urbanisation, pollution, deforestation and commercial fishing. Due to such factors, the rate of species extinctions is accelerating. More species are now threatened with extinction than ever before in human history.

‘With biodiversity loss, we not only lose nature, we lose some of our best defences against climate change,’ said Myron Peck, who leads the Department of Coastal Systems at the Royal Netherlands Institute for Sea Research (NIOZ). ‘Our oceans, forests, peat bogs, and wetlands all act as natural carbon sinks, absorbing harmful carbon from the atmosphere.’

It’s clear that it’s impossible to address biodiversity loss without tackling climate change, and equally impossible to tackle climate change without addressing biodiversity loss. This is  acknowledged in the new EU Adaptation Strategy in February 2021.

‘We are living in a world where everything is interconnected,’ said Elisa Furlan, an environmental scientist at Italy’s Centro Euro-Mediterraneo sui Cambiamenti Climatici. ‘Climate-related and human-made hazards have become increasingly systemic, the result of the complex and dynamic interactions happening among human, economic, political, and natural systems.’

Because of this interconnectedness, we’re essentially left with a vicious circle where the increasing temperatures and extreme weather brought on by climate change causes biodiversity changes and loss of ecosystem services, which subsequently leads to more climate change, which causes more biodiversity loss, and so on.

How do we stop this downward spiral?

According to the World Wildlife Fund, nature-based solutions harness the power of nature to address climate change. Common examples include restoring and protecting forests and wetlands, bringing nature into urban settings, restoring coastal areas, and implementing best practices in sustainable agriculture. Not only do these solutions prevent biodiversity loss they also build resilience against a future of rising sea-levels, desertification, extreme flooding and wildfires.

A good example of nature-based solutions at work can be found right here in Europe, in the Marine Protected Area (MPA) networks established throughout the EU seas with nationally designated areas and the EU network called Natura 2000. However, while these areas have made headway in terms of protecting critical species today, according to Peck, they’ve stopped short of implementing the measures needed to ensure their resilience for a future defined by a changing climate. ‘There simply can’t be long-term restoration without regulation,’ he said.

Furlan agrees, noting that coastal areas are particularly vulnerable to the effects of climate change. ‘Marine areas are subjected to the one-two punch of natural stressors, like waves and storms, and to the pressures created by changes in land use, the shipping industry, and mass tourism,’ she said.

Add to this a general lack of understanding about how these factors affect marine life, and the inadequate governance mentioned by Peck, and what you’re left with is a critically important habitat that has been left to fend for itself.

‘Marine and coastal ecosystems support a large proportion of the world’s biodiversity and play an important role for society by, for example, regulating climate, providing food resources, and contributing to our well-being through cultural and recreational opportunities,’ added Furlan. ‘By taking this for granted, we’ve set the scene for a perfect storm.’

Gathering blue intelligence

For Peck, Furlan, and others, priority must be given to providing policymakers with the nature-based solutions needed to protect our critical coastal ecosystems for the long-haul.

Leading the EU-funded Horizon 2020 FutureMARES, Peck and his team is researching the potential benefits of introducing habitat-forming species like reef-building corals and canopy-forming macroalgae into coastal areas.

‘Our main concern is to restore biodiversity, and that process starts by making these damaged habitats healthier,’ he said. ‘After all, a healthy habitat has a better chance of withstanding climate change than a depleted one.’

Similarly, the EU-funded Horizon 2020 MaCoBioS project is providing evidence-based guidance that policymakers can use to halt the loss of biodiversity in Europe’s marine areas. ‘Delivering on the targets set out in the EU 2030 Biodiversity strategy and 7th Environment Action Programme starts with understanding the interrelationship between climate change, biodiversity and ecosystems,’ explained Furlan, who helps coordinate the project.

To address this knowledge gap, the project is studying several critical marine habitats, including the coral reefs of the Caribbean, the seagrass beds of the Mediterranean, and the kelp forests of the North Sea.

‘Each of these unique areas are subjected not only to climate change, but also fishing, recreation, and pollution,’ said Furlan. ‘As such, they serve as a lens for examining how these pressures lead to a decline in biodiversity and how such a decline impacts connected ecosystems.’

With this information, researchers will quantify the combined impact that human activities and climate change have on these ecosystems.

‘Our goal is to create models that decision-makers can use to implement effective, nature-based mitigation actions that ultimately results in resilient marine habitats,’ added Furlan.

Learning today to prepare for tomorrow

Further north, researchers are working to understand and predict changes in Arctic marine biodiversity. They are studying its implications on fisheries (the economic lifeblood of many Arctic communities) and carbon sequestration, which has important implications on the global climate.

‘We still don’t have a good understanding about how marine biodiversity in the Arctic responds to climate-related pressures like temperature, salinity, and pH, as well as land- and ocean-based stressors such as invasive species, pollution, and fishing,’ said Marja Koski, a researcher at the National Institute of Aquatic Resources, part of the Technical University of Denmark, and coordinator of ECOTIP. ‘How organisms will respond to combinations of these stressors is largely unknown.’

According to Koski, the current method of describing and modelling marine biodiversity has its limitations. In fact, despite a century of detailed taxonomic studies, over 90% of Arctic marine species are currently thought to be undiscovered. This means we can’t predict the consequences that a change in, for instance, the composition of plankton communities will have on carbon sequestration and fisheries.

‘Our knowledge is still fragmented in terms of how biological changes interact with human decisions and behaviour, including how fisheries are managed in the Arctic,’ explained Koski. ‘This limits our ability to jointly develop adaptation options with local communities and Indigenous Peoples in the Arctic.’

To fill this knowledge gap, the project is using new molecular methods on environmental DNA (eDNA) to detect invasive species, in the Arctic. eDNA refers to DNA that can be collected from the environment (for example water samples). ‘The use of eDNA for species monitoring is revolutionary as it saves time, costs, and workload without impairing the target organism or the ecosystem,’ noted Koski.

ECOTIP is also investigating the concept of ecosystem tipping points, irreversible changes of ecosystems, like the possible melting of the Greenland ice sheet. ‘Such changes have a cascading effect across the entire ecosystem, which ultimately impacts fisheries and the ocean’s ability to act as a carbon sink,’ explained Koski.

According to Koski, having information like this is key to being able to predict and mitigate the effects climate change has on biodiversity – and the effect biodiversity has on climate change. After all, if we don’t understand the mechanisms of why things happen, we cannot even fathom predicting what might happen in future.

‘We can observe the changing distributions of zooplankton in the North Sea, for example, but if we don’t know what causes the distribution shifts, how can we implement effective regulations,’ asks Koski? ‘Being able to extrapolate what we do know to other areas and conditions is how we stop the cycle of biodiversity loss.’

Deepening knowledge of the many factors spinning this cycle is the first step. And, as a result, we are better positioned to project the changes we see today to future scenarios – helping us prepare for the changes yet to come.

The research in this article was funded by the European Union’s Horizon 2020 research and innovation programme. If you liked this article, please consider sharing it on social media.

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Cures for the health insurance enrollment blues

Some countries with national health insurance plans face a basic problem: Not enough people sign up for those programs, and the ones who do tend to have worse-than-average health. That is a public health matter, but also a fiscal issue. When more healthy people enroll in health care plans, and thus pay premiums, those plans gain a better fiscal footing.

What’s a good way to address this challenge? A recently published study in Indonesia led by MIT economists yields new insights, which could apply globally. The study involves a three-pronged experiment in which people received either encouragement to enroll through subsidies, assistance with the signup process, or information about the program’s benefits.

For starters, full subsidies for program participants increased enrollment by 18.6 percentage points, the experiment revealed.

“We do find that subsidies make a difference,” says Benjamin Olken, an MIT economist and co-author of the paper detailing the experiment’s results.

But the experiment also produced what Olken considers an equally important insight: The sheer challenge of navigating the health insurance signup process is a serious issue. Registration assistance alone increased signups by 3.5 percent, but many more people tried and failed to enroll in the program, underscoring how much the administrative capacity of countries — keeping track of people and helping them with the bureaucracy — makes a difference.

“One of the lessons of this paper is the importance of the infrastructure of the state,” Olken says. “Investments in that underlying infrastructure are not the most exciting thing, but they are really critical.”

The paper, “The Challenges of Universal Health Insurance in Developing Countries: Experimental Evidence from Indonesia’s National Health Insurance,” was published in the September issue of the American Economic Review.

The co-authors are Abhijit Banerjee, the Ford International Professor of Economics at MIT; Amy Finkelstein, the John and Jennie S. MacDonald Professor of Economics at MIT; Rema Hanna, the Jeffrey Cheah Professor of South-East Asia Studies at the Harvard Kennedy School; Olken, the Jane Berkowitz Carlton and Dennis William Carlton Professor of Microeconomics at MIT; Arianna Ornaghi, an assistant professor of economics at the Hertie School in Berlin; and Sudarno Sumarto, an economist with the Indonesian government’s National Team for the Acceleration of Poverty Reduction (TNP2K) and a researcher at the SMERU Research Institute in Jakarta, Indonesia.

Temporary subsidies, long-term impact

Indonesia introduced its national health insurance policy in 2014. The program completely subsidizes care for the very poor and counts on better-off citizens to enroll and pay monthly premiums, to fund much of the program. The system resembles those in several other countries, including Ghana, Kenya, the Philippines, and Vietnam.

All these countries, including Indonesia, require that citizens enroll in their health insurance programs, but they only lightly enforce that mandate. One year after Indonesia’s program launched, fewer than 20 percent of targeted citizens had enrolled in it, and the ratio of claims to premiums received was 6.45 to 1.

The genesis of the MIT-driven experiment came from discussions between the research team and Indonesian government officials, in an effort to find ways to spur enrollment. The researchers ultimately conducted their three-part experiment with about 6,000 Indonesian citizens, starting in 2015 and then tracking participants’ enrollment status for about 20 months after the experiment ended.

The first arm of the experiment provided both full- and half-size, year-long subsidies to participants, while comparing the outcomes to a control group. While logic would predict an enrollment boost due to subsidies, as indeed occurred, the experiment produced an intriguing twist — once the subsidies end, people who received them are twice as likely to pay for coverage as people who never received a subsidy.

“One encouraging thing about that result is that temporary subsidies have long-term impacts,” Olken says. “People join the program, get their coverage totally for free for a year, and then have to start paying, and many of them continue paying. … They recognize there’s value in this program.”

A key related point is that by attracting more premium-paying participants this way, the subsidies draw largely healthier people into the program. This helps limit the problem of “adverse selection,” in which people in generally worse health are more likely to opt into health insurance programs, creating fiscal pressure by incurring relatively more expenses for those programs. Adverse selection is one reason health insurance mandates exist, even if they are not always closely enforced.

“Temporary subsidies can reduce this kind of adverse selection,” Olken says.

When failure is an option

Meanwhile, the second prong of the experiment, which offered in-person assistance to people trying to enroll in the health insurance program online, offered its own revealing data points. The researchers discovered that more than half of all people who attempt to enroll do not ultimately succeed.

“I don’t think that’s something anybody exactly knew, because they hadn’t measured it before,” Olken observes.

That suggests the enrollment process itself matters greatly. More broadly, Olken notes, it also suggests the bureaucratic capacity related to these large national programs is a highly important factor in their success. Governments have to correctly identify citizens while also developing methods to help them enroll more smoothly, the researchers conclude.

“Making it easier for people to [enroll online] at home only works if you have the underlying administrative infrastructure,” Olken says. “These various social protection systems are built on a foundation, and part of that foundation is having information about who’s who, and investments in that infrastructure.”

Perhaps surprisingly, the third part of the Indonesian experiment, in which people were provided with information about the program and its benefits, appeared not to affect enrollment rates — even though many people might not know much about the policy in the first place.

“Experience is different than basic information,” Olken says, acknowledging that the latter did not spur people to obtain coverage.

In all, the success of national health insurance plans depend on many factors, from a government’s ability to bear costs to the effectiveness of a country’s health care system. But given how critical enrollment is to the fiscal firmness of such systems, the Indonesia experiment reveals promising avenues of improvement — and indicates the need to study more about enrollment issues in countries around the world.

“We need to understand what can we do about this piece of it,” Olken says.

The study was funded, in part, by the Australian Department of Foreign Affairs and Trade and the Korea International Cooperation Agency.

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