You Can’t Treat Tuberculosis With Platitudes

One of the most striking parts of the World Economic Forum’s annual meeting in Davos, Switzerland, is the funicular, which takes billionaire revelers on a steep, scenic climb from the village below to the top of the Schatzalp, also known as the Magic Mountain. There, typically in thick snow and bright sunshine, they sip champagne outside a converted tuberculosis sanitarium—the very one immortalized in Thomas Mann’s 1924 novel, The Magic Mountain—which once housed dying, mostly poor Swiss.

Of all infectious diseases, few are as tightly connected to poverty and shame as tuberculosis, or TB. Although wealthy and famous people, from (some have posited) King Tutankhamen and Voltaire to Eleanor Roosevelt and Paul Gauguin, have suffered from the disease, most of its victims have been anonymous, people living in crowded housing, imprisoned, or whose bodies were weakened by malnourishment, alcoholism, drug use, HIV infection, or other diseases. In fact, TB was one of the first diseases tied to urban poverty at the beginning of the 20th century; as the New York City physician S.A. Knopf wrote in 1900, “If I should be asked what conditions are most conducive to the propagation of tuberculosis, and especially pulmonary consumption, I would have to reply: the conditions that prevail in the old-fashioned tenement houses as they still exist by the thousand in this and other large cities.”

The link between TB and poverty has enveloped the disease in a cloud of shame. It is no coincidence that the Magic Mountain sanitarium was built in what was then one of the most remote places in Europe. Typical for a TB center, it was meant to isolate the disease victims from the rest of the world. Even today, shame silences would-be advocates, sends individuals in need of treatment into hiding, discourages investment in novel therapies and vaccines, and places support for TB programs near the bottom of most governments’ already paltry health budgets.

Making matters worse, organizations meant to address TB—from various bodies at the World Health Organization (WHO) and U.S. Centers for Disease Control and Prevention to the Stop TB Partnership and the Treatment Action Group—have squabbled over policy, science, and money, rarely presenting a coherent voice to the world. For decades, WHO was at the helm of TB prevention and treatment efforts and was functionally tasked with steering a boatload of angry dissidents among which the U.N. agency had zero credibility.

But things might finally be changing. In recent months, the community of TB organizations, physicians, patient advocates, U.N. agencies, and scientists has grown remarkably united, and it has come together behind a series of “asks” for radically improving research, medicines, vaccines, and patient treatment, including prevention efforts based on human rights, new diagnostics, new drugs, a genuinely effective vaccine, and more funding, with clear accountability for how that money is spent. Perhaps most importantly, the community is combating the shame that surrounds TB and demanding global attention for the disease.

These efforts will come to a head at the United Nations General Assembly, which opens in New York this week, and will be preceded by a special session on tuberculosis. In its first 54 years, the U.N. General Assembly never convened a high-level meeting focused on disease. Then, in 2001, when HIV was treatable in wealthy countries but medicines for it were unaffordable across Africa and other hard-hit regions, it convened a historic special session that called for greater access to anti-HIV medicines, testing, family support, and health care worldwide.

Coming alongside genuine financial commitments from the G-8 nations, Bill & Melinda Gates Foundation, and the World Bank, the special session and resulting U.N. declaration were effective. In the years since, billions of dollars and a vast infrastructure for treating the disease have brought HIV treatment to more than 18 million people and cut the number of people dying from HIV by 52 percent from its 2004 peak.

The TB community is hoping that the U.N.’s attention will do for tuberculosis what the 2001 special session did for HIV/AIDS. Sadly, it will not.

Treatment of AIDS had the positive side effect of reducing cases of TB. The AIDS epidemic had caused a spike in tuberculosis cases as the bacteria took advantage of HIV-ravaged bodies. Soon, extremely antibiotic-resistant forms of TB popped up all over the world. Global efforts to control TB, in part by reducing the burden of AIDS, have averted 54 million deaths since 2000. And that’s very good news. But the rate of improvement has slowed over the last few years to about a 2 percent reduction in deaths annually. At that rate, tuberculosis will remain a global killer well past the middle of this century.

Indeed, “TB is still the biggest infectious disease killer in the world,” Eric Goosby, the U.N. special envoy on TB, pointed out during a Geneva press conference at WHO headquarters last week. Drug-resistant forms of tuberculosis have spread well beyond the boundaries of HIV outbreaks, afflicting people in general populations worldwide. Almost half of the drug-resistant TB cases last year were in three countries: India, China, and Russia.

Several factors make the disease particularly tricky to wipe out. First, TB is airborne, and it is not uncommon for families to fall ill together. Indeed, in most cases, the afflicted become ill directly after exposure to an ailing TB victim, and according to a recent study, the average incubation time for tuberculosis is just months to two years after infection.

At the same time, more than 20 percent of the world population is estimated to carry a latent tuberculosis infection, with thousands of bacteria hidden inside a concrete-hard protective encasement tucked away somewhere in the body. They have no symptoms, are unaware of their infection, and may go to their graves having never suffered the disease. Under conditions that are poorly understood, however, longtime infections may suddenly turn aggressive, with bacteria bursting from the protective shell and filling the lungs, bloodstream, or dozens of other organs and tissues with Mycobacterium tuberculosis. When that happens, the individual will finally start to feel sick, losing weight, becoming fatigued, and experiencing breathing problems if the infection is in his or her lungs. Only when the symptoms become severe do most victims of TB seek medical care. Even among obviously ailing tuberculosis sufferers, according to a recent report, more than a third of those who fell ill with the disease in 2017 never sought or received treatment.

And this leads to another factor preventing the eradication of TB: Diagnostic tools for the disease are rather poor. Doctors in most of the world rely on strategies used for decades. Sputum tests go back more than a century, wherein a technician studies a spit sample under a microscope. More sophisticated, but also very old, tests involve growing a colony of bacteria from a sputum sample, but it takes 12 weeks to do so, by which time the patient may be dead. X-rays can spot cavities in the lungs or other locations where the bacteria has devoured tissue, but by the time such markers show up, the disease will already be quite far along. In 2010, a new molecular test that can produce a diagnosis within two hours was introduced, but countries have been slow to adopt it for a variety of reasons. And although some biotech companies have tried to develop new ways of diagnosing TB, especially in children, none of the novel products shows sufficient reliability or sensitivity.

Unfortunately, if TB is not diagnosed and goes untreated, it kills more than 70 percent of its victims. For those who do receive treatment, 82 percent survive. But the medical toolkit for the disease is pretty lousy, and few resources have gone toward the invention of new drugs, vaccines, diagnostic kits, and supportive therapy. In most of the world, TB is detected, contained, and treated pretty much the same way in 2018 as it was in 1978. Only two new drugs, both taken orally and both expensive, have been added to the arsenal in this century: bedaquiline and delamanid. Two other drugs have been removed from standard protocols—kanamycin and capreomycin—because they have to be injected daily and cause terrible side effects, including kidney failure, loss of hearing, dizziness, seizures, and loss of feeling in the hands and feet.

Even straightforward cases—patients being treated for first-time TB infections who do not have a strong drug-resistant strain—are hard to manage. Patients must take two or more drugs daily for six months, drawn from a list of old and cheap treatments dating to the mid-20th century: isoniazid, rifampin, ethambutol, and pyrazinamide. Adherence to the daily schedule is crucial (otherwise, the bacteria will become drug resistant), but side effects include nausea, dizziness, severe stomach pain, fatigue, yellowing eyes, liver damage, and headaches, so it is understandable that many patients slip.

If the individual’s tuberculosis becomes (or starts out as) resistant to one or more of the front-line drugs, doctors will introduce powerful antibiotic fluoroquinolones, bedaquiline, and delamanid. These patients face a daily cocktail of six to eight pills and possible injections, all of which produce side effects and pain. Treatment can be so odious, in fact, that most patients must register with an individual who directly observes and affirms their daily pill-taking. Even so, last year, 45 percent of patients who were treated for the most drug-resistant TB died.

In short, the clock is ticking, and the world desperately needs better solutions for TB: new diagnostics, new drugs, and a vaccine. But the ecosystem of research and development is stacked against tuberculosis.

First, with international spending on TB so paltry, the bulk of anti-tuberculosis funding comes out of individual countries’ budgets. That means that poor and middle-income nations, hard-hit by TB and with meager resources to address it, face most of the costs of doing so.

Second, because most of the disease’s victims are poor and living in underdeveloped or emerging market countries, profit margins on products for the disease will never be wide enough for the pharmaceutical and biotechnology industries to want to develop them. And those drugs that do get made are too expensive for the victims to use. For example, Japan’s Otsuka discounted the newest treatment, delamanid, to $1,700 per course. But that cost far exceeds the pennies-per-dose price of the older therapies.

According to the New York-based Treatment Action Group, total worldwide spending in search of new medicines, vaccines, and diagnostics to address TB is merely $726 million, with private sector spending representing just 11 percent of that total. Given that the top 20 pharmaceutical companies spent a combined $97.2 billion on research and development in 2017, the $78.5 million they allotted to TB is barely a footnote.

All tolled up, the world is facing a funding gap for the treatment and research of TB of $3.5 billion this year alone, according to estimates by WHO and the Global Fund, “a figure that will nearly double by 2022. More resources from domestic and international sources, high-level political commitment, and investment in research and development are needed.”

The TB community has been readying for the U.N. special session for well over two years now, anxiously watching the rising toll of drug-resistant tuberculosis and hoping to convince world leaders to bring new technology, innovation, and money to the fight. Changes over the last 18 months in WHO leadership, as well as inside its TB program, ushered in renewed dialogue with the Union, an organization founded in 1920 to fight tuberculosis; the Stop TB Partnership, an umbrella group for interested companies and nongovernmental organizations; Médecins Sans Frontières (MSF), the Nobel Peace Prize-winning medical providers; and allied medical and scientific associations. This spring, the groups were able to reach an agreement on the demands they would make of the U.N. system.

The Stop TB partnership released a statement noting that despite progress since 2000, “[t]here are still 10 million people who get sick with TB every year. TB remains the most significant single infectious disease killer, causing 1.6 million deaths in 2017.” The statement, which also mentioned last year’s slight decline in cases, went on to ask: “[D]oes it matter if we have 10 million new cases, or 10.2? Does it matter if the numbers are 1.6 million deaths or 1.7? Does it matter that we found and treated 6.3 or 6.4 million people with TB? For all of our collective efforts and new diagnostic tests we used, we were able to put in 2017 only 10,000 more people on treatment for drug-resistant TB, while hundreds of thousands remain suffering. These are people we are failing to help.”

The rest of the TB community agreed with the tone and details in that statement, which anticipated a formal declaration from this week’s summit about how the U.N. would fight TB. But this summer, the U.S. delegation blocked the U.N.’s formal declaration procedure, under which General Assembly leadership would usually work with key stakeholders to create consensus among members in advance of the summit and hammer out language for a statement that would come up for a vote sometime after the General Assembly opens. U.S. intransigence became so intense that there was concern that no U.N. declaration on any topic would be ready for the 193 member states to endorse.

The issue in the particular case of TB was pharmaceutical profits and the World Trade Organization (WTO). Under the WTO’s Doha Declaration, countries may bypass patents and allow competitors to create cheaper versions of name-brand drugs if the product in question is pivotal to addressing a public health emergency. The relevant WTO language is called the Agreement on Trade-Related Aspects of Intellectual Property Rights, or TRIPS, and it was used previously to push U.S. and European anti-HIV drugmakers to allow companies in India to produce generic versions of their medicines, driving the cost of a year’s treatment down to $75 from a high of many thousands of dollars.

Because the development of new drugs and diagnostic tools is critical to fighting TB, MSF and the Stop TB Partnership argued that any U.N. declaration should clearly underscore the need for affordable medicines and the right to implement TRIPS if necessary. Such language, however, was anathema to the pharmaceutical industry and U.S. President Donald Trump’s administration. Adrian Thomas, the vice president for global public health and access at Johnson & Johnson, warned that “if drug makers are unable to make returns on their investments when they bring medicines to market, they may be deterred from developing the next generation of therapies.” And a group of legal scholars soon countered that “the development and distribution of drugs to fight tuberculosis raise two questions: How much profit is enough? And at what cost? … The second is easier to answer: the cost of excessive pharmaceutical industry profits is unnecessary human suffering and death at a staggering scale.”

Eventually, the countries reached a compromise and drafted the final 16-page declaration, “United to End Tuberculosis: An Urgent Global Response to a Global Epidemic.” The document lays out the case for TRIPS in its lengthy list of facts about the TB crisis, but it does not call for any specific action for implementing it. Nor does the declaration suggest any clear chain of command: Who would be in charge of an escalated war on tuberculosis, collecting money, deciding how it should be spent, egging on pharmaceutical innovators, and steering the ship through troubled waters?

Those failures have led to some pessimism.

“I would be really surprised if the high-level meeting resulted in any significant new governance or accountability structures for TB,” Mark Harrington said after the text of the declaration was released. Harrington cut his teeth as an ACT UP AIDS activist and received a MacArthur Foundation grant for the creation of the Treatment Action Group, which tracks R&D for HIV, hepatitis, and TB. He’s also a member of the Stop TB Partnership. Harrington predicts that the U.N. will not challenge WHO’s leadership on tuberculosis. “The WHO is not going to change its governance to include the private sector, NGOs, or civil society. There is not going to be any new money for TB,” he said. “There will be no new accountability mechanisms, and no one new will be in charge of anything new, because it’s unlikely that anything really new is going to come out of the [high-level meeting].”

Two years ago, a very energized group of medical organizations, international agencies, and humanitarian associations came together under the leadership of the United Kingdom to fight for passage of a tough U.N. declaration on antibiotic resistance. The advocates, drawn from the highest levels of British health governance, faced the same problems now confronting those fighting TB: namely, pharmaceutical patents and profits and governance. Both issues were, in the final documents, sidestepped. And today, it is impossible to identify any agency or individual who is in charge of implementing the declaration’s lofty goals.

According to the Pew Charitable Trusts, as of June “approximately 42 new antibiotics with the potential to treat serious bacterial infections are in clinical development.” And of those, few potentially target any aspect of bacteria that the microbes haven’t already developed resistance against. Further slimming the odds of finding a miracle cure to antibiotic-resistant bacteria is that, historically, only about 1 in 5 drugs that enter into clinical trial will be approved.

Meanwhile, since 2003, most of the top antimicrobial manufacturing companies have quit that part of their businesses, diverting resources to other types of drugs and vaccines. That leaves only four big players on the field: Merck, GSK, Roche/Genentech, and, exclusively making anti-fungal compounds, Astellas. And there is just one reason the drugs playing field has been whittled down so drastically: profits.

In the end, if the experience with antibiotics is any guide, the United Nations may not be capable of standing up to the $1.1 trillion pharmaceutical industry or the Trump administration. And organizing worldwide efforts to save millions of lives requires a chain of command that features genuine cooperation among the U.N., large multilaterals such as the Global Fund, and thousands of dedicated NGOs that are fighting diseases on the front lines. But developing such a system does not appear to be a priority of the U.N. The great success in fighting HIV, pushed by the U.N., appears to be an exception to the rule.