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Public Health

Difficult progress

Persistent poverty expands uncertainties around research into TB drugs and treatments

From Cancun (text) and Kibaha (photos)*

Evelyn Hockstein Nurdinir Mayoyo delivers a bundle of vegetables to improve the diet of Celestine Banja, who is undergoing treatmentEvelyn Hockstein

The hope of getting new tuberculosis (TB) drugs in hand quickly did not come true. The Stop TB Partnership, a branch of the World Health Organization (WHO), forecast than in 2006 at least one new drug for one of humankind’s oldest diseases would be ready by 2010. “We failed,” recognized Christian Lienhardt, one of the representatives of the Stop TB Partnership at the TB congress held in early December in Cancun, a beach town in southeast Mexico, “but we’re closing up on our targets.” For the first time ever, 20 new molecules apparently able to stop Mycobacteria tuberculosis colonies are under development at the same time. Most are still undergoing preliminary animal trials, but three are already at the initial stage of safety and efficacy trials with humans, another three are in the second stage, and two are in the last stage. An optimistic outlook points to two or three new drugs being ready for registration with government bodies and release for widespread use by people in 2015.

“This is an historical opportunity to change the way we treat TB,” emphasized Zhenkun Ma, the scientific director of the Global Alliance for TB Drug Development (TB Alliance), which congregates research institutes, enterprises and governments in the pursuit of new drugs against the disease that killed 1.8 million people in 2008, including 500 thousand also infected with HIV, the Aids virus. Four and a half thousand people, on average, die from TB daily or one every 20 seconds. In Brazil, according to a WHO report released in early December, 92 thousand people (including 13 thousand with HIV) found out in 2007 that they had TB. This document acknowledges the progress of control programs, but warns that the rates of detection and of successful treatment are still below the global levels proposed by the WHO.

Even if their toxicity level is acceptable, if they do not interfere with other medication and if they are proven effective against TB bacteria, the new drugs will have to overcome other barriers before reaching at least part of the 9 million people diagnosed with TB every year. What one hopes the new drugs will provide is simpler and shorter treatments than those currently available, which consist of four antibiotics, to be taken for at least six months. “Shorter treatments imply in more people adhering to treatment, a higher rate of cure, fewer sacrifices for the patients and a lower risk of drug-resistant strains of bacteria emerging,” commented William Wells, TB Alliance’s market access director.

The Mycobacterium tuberculosis strains that are most resistant to the antibiotics most often used to fight TB are a source of concern for several reasons. First, because they spread throughout the world: they have been found in at least three Brazilian states (Rio de Janeiro, Mato Grosso and Goiás). Second, the severest forms of the disease, requiring longer lasting and more intensive treatment, have tended to be under-diagnosed. “Less than 3% of the estimated 500 thousand cases of multi-resistant TB are detected and treated,” stated Jeremiah Chakaya, director of the Kenya Medical Research Institute, at the Cancun congress. The drugs currently available to treat multi-resistant TB, to date, cause strong side effects and are few and expensive.

Another expectation surrounding the drugs currently in trial is the possibility of using them in combination with other medication, especially the anti-retroviral drugs used to halt HIV, which affects 1.4 million of the people with TB (15% of the total). At present, antibiotics reduce the effect of the HIV medication, putting those who suffer from both diseases or that are willing to treat both in a difficult situation. “TB kills people with HIV,” stated Lee Reichman, a professor of preventive medicine at the University of New Jersey, United States. “It’s one patient, two diseases and just one healthcare system. The TB and Aids prevention and treatment programs should work together, but this doesn’t always happen.” Additionally, the new drugs will have to have large-scale production and be affordably priced, even in the world’s poorest countries, home of most people with TB, who generally live in precarious housing packed with many more people.

“If you get no fresh air and sunlight you’re far more likely to contract the disease,” says Peg Willingham, external policies director of Aeras Global, a non-profit organization that is heading the research that may lead to more effective vaccines than the BCG one to prevent latent infection and the emergence of the disease. Used since 1921, BCG no longer yields satisfactory results. In collaboration with universities, pharmaceutical companies and governments, Aeras coordinates the research on 6 of the 14 new vaccines currently being developed – four of which are undergoing human trials in Africa. Peg believes that the evaluation studies seeking a new, more effective, safe and accessible vaccine than BCG may be ready by 2016. However, in a chat with journalists, she warned that “there is no guarantee of success in medical research.”

Evelyn Hockstein In Kibaha, Tanzania, Rajabu Saidi supports Mariam Abdala, who is now walking again after being bedridden for months with TBEvelyn Hockstein

This caution is not without reason, as the obstacles are plentiful. According to her, the trials of the third and last stage of the evaluation of the efficacy and safety of just one of these potential new vaccines can cost as much as US$160 million and involve 5,000 voluntary participants during the course of four years. One of the challenges is getting the support of government bodies, which may take years to respond to requests for carrying out clinical trials and to grant the drug’s final registration for use in public health campaigns afterward, following successful testing.

Logistical difficulties are added to governments’ lack of commitment to medical research. As African countries have a shortage of laboratories, microscopes, physicians and nurses capable of confirming the diagnosis – the first step toward treatment – it is difficult to conduct new drug evaluations in them. In an article published in October 2009 in Human Vaccines, Antony Hawkridge, the Aeras coordinator for Africa, who works from Cape Town in South Africa, commented that the clinical trials depend on access to populations with a high rate of TB and on one’s capacity to recruit thousands of people within a short time span, to keep these participants within the study, and to detect and document other health problems that may arise during the course of these trials. Occasionally the very institutions in charge of trials supply or reinforce their clinical trials infrastructure or set up the labs that are indispensable to assess the safety and efficacy of promising molecules.

The English physician Anthony Harries is highly familiar with the link between TB and one of its chief causes and source of added complications: poverty. He currently lives in Paris and is a senior advisor to the International Union against TB and Pulmonary Diseases (the Union), an association with 10,000 members from 145 countries. He is also a professor of medicine in London. For 22 years, Harries worked as a doctor in Malawi in southeast Africa, one of the world’s poorest nations, with one of the highest rates of TB prevalence (12% of the population). There, he confirmed the obvious: with no money, poor people eat little and badly. Malnutrition and the scarcity of protein and of vitamins weaken the body’s defenses against the microorganisms that cause diseases like TB and Aids. “These deficiencies are more severe among people with a lower body mass,” he noted. In one of his studies, Harries noticed that the risk of dying from TB in the first four weeks of treatment ranged from 6.5% to 11% depending on whether the patient had a bigger or smaller body mass.

In Malawi, those who cough continuously and suspect that they have caught TB may have to go a very long way to get to a healthcare center for treatment. According to Harries, sick people often postpone the trip not only because of the distance, but also because they fear the social isolation that goes hand in hand with suffering from TB, and because they do not trust allopathic medication and prefer the advice and drugs proffered by traditional shamans. The English physician witnessed stark contrasts. Malawi has 13 million inhabitants and 270 physicians. Annual health spending per capita is US$15 and there are 26 thousand new cases of TB a year. The United Kingdom, on the other hand, has 60 million people and 135 thousand physicians. Annual health spending is US$2,500 and new cases of TB total only 6,700 a year.

“The voices of society at large must become stronger,” says Harries, who witnessed other silent causes of TB in addition to the colonies of bacteria in the lungs that cause fever and night perspiration. Most of a group of 770 people whom he saw to lived on less than US$10 a month, in houses with no running water or electricity. Even so, according to Jeremiah Chakaya, the inhabitants of many African countries have to pay the equivalent of US$10 or US$20 to get an X-ray taken to confirm whether they have TB. Merely new drugs or new treatments, even if they are outstanding, may prove insufficient to sever the link between TB and poverty, a subject heavily debated at the Cancun congress. In one of the conferences, Mario Raviglione, director of the WHO’s TB department, recalled that the rate of treatment success peaked in 2007, at 87%, 78% of the cases being detected in the Americas and 47% in Africa. However, this will only progress if healthcare systems improve, and if there is greater social protection and reduction of poverty.

The difficulty in the struggle against this disease is lending strength to a new approach in the development of drugs, one that is no longer confidential and conducted only by major pharmaceutical companies, but open and based on the cooperation of governments, philanthropic organizations, universities and enterprises, with the mediation of NGOs. These arrangements go under the name of public-private partnerships, including organizations such as TB Alliance, Aeras Global and New Medicines for Tuberculosis. The limitations of each participant are now acknowledged and shared. “The private-sector companies are unable to justify the investments and academia doesn’t know how to develop new drugs all the way to the end,” William Wells acknowledged. “We don’t have enough money to do everything on our own” says David Barros, from GlaxoSmithKline (GSK), a company that set up a trials program for four new drugs with TB Alliance and that plans, in 2010, to expand its strategy of open and shared research on new, broad spectrum antibacterial drugs. “New medication against diseases such as TB, to which insufficient attention has been paid, has to be good business for all involved,” Barros reiterated.

The discoveries are also communicated publicly instead of taking place in secret, as is the case of most drugs for other illnesses. The limits and possibilities of using moxifloxacin, an antibacterial drug for pneumonia and respiratory infections that is in the advanced trials stage with TB Alliance, have been presented and heavily debated in scientific articles, some of which are freely available. In June 2009, the New England Journal of Medicine published the positive results achieved in the treatment of multi-resistant TB with TMC207, a new compound. The trials led to an agreement between the pharmaceutical company Tibotec and TB Alliance, enabling the company to license the drug, if it is approved by the regulating agencies, without charging royalties, as a means of expanding treatment of the severest forms of TB.

Other types of collaboration are also working. Connections with healthcare professionals experienced in the treatment of other infectious diseases such as malaria and Hansen’s disease in places where TB is also common have made it easier to hold trials of new TB vaccines. “It is not as difficult to establish these collaborations as we had expected,” celebrates Peg Willingham, from Aeras Global. The Union has mobilized private healthcare clinics in Indonesia to enhance their TB control services and nine million students in China, who were taught how to identify TB symptoms among their relatives and to ensure that they were seen to by local physicians.

*Fioravanti attended the 40th Union World Conference in Cancun, Mexico, at the invitation of the Stop TB Partnership and the National Press Foundation. With the aid of the World Health Organization, Evelyn monitored former TB patients who help to treat those who still suffer from the illness in Kibaha, Tanzania.

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