How can treatments be improved?

Tuberculosis is neither a disease of the past nor is it overcome, quite the contrary. Some data are shocking: the World Health Organization (WHO) estimates that a quarter of the world’s population is infected and that more than 10 million people develop the disease each year. Approximately one and a half million people die annually from this disease, and 10% are children.

Doctors Without Borders includes tuberculosis in the group of “forgotten diseases”, since 95% of cases occur in poor countries. The eight countries that in 2020 reported two-thirds of the world’s cases are, in descending order, India, China, Indonesia, the Philippines, Pakistan, Nigeria, Bangladesh and South Africa, but it also occurs in the most socially disadvantaged layers of wealthy nations. Therefore, it exists and constitutes a global public health problem.

The disease is aggravated by risk factors such as HIV infection, covid-19 and diabetes. Also with malnutrition, dirt, overcrowding, drug use, alcoholism, smoking and other socio-environmental factors.

In fact, the impact of the covid-19 pandemic has been devastating for tuberculosis, going back to scenarios of years ago in the diagnosis of new cases and in the control of the disease through contact studies. The objective, now, is to return to 2019 levels.

What is being done to combat this situation?

The WHO has deployed an “End Tuberculosis Strategy” worldwide, with milestones (2020-2025) and objectives (2030-2035) that evolve based on different periods of time.

Milestones (2020–2025)

• 35% reduction in the number of deaths in 2020 compared to 2015. Only 9.2% achieved.

• 20% reduction in the incidence rate in 2020 compared to 2015. Only 11% achieved.

• Ensure that no person with TB or their family incurs catastrophic costs (more than 20% of annual household income) due to TB.

Objectives (2030-2035)

• Successfully treat 40 million people with tuberculosis between 2018 and 2020. Only 50% (20 million) achieved. Of these, 1.4 million were under 15 years of age (41% of the child treatment sub-goal)

• Preventive treatment for 30 million people between 2018 and 2022. Only 29% (8.7 million) achieved.

• 13 billion dollars (about 12 billion euros) are needed to guarantee universal access to tuberculosis prevention, diagnosis and treatment services.

These goals and objectives are basically not met due to insufficient resources, social commitment and political will. In the last 20 years, some progress has been made in the diagnosis and treatment of tuberculosis, but the implementation in the field of these diagnostic and therapeutic resources does not reach all sick people.

An optimal vaccine is not yet available, and treatments are evolving, albeit not at the speed required. In addition, in the case of children, there are a series of added problems.

Why should the treatment of childhood tuberculosis be improved?

Tuberculosis is a curable disease, also in minors, but said cure depends on adequate compliance with treatment. This includes the use of three to four different anti-TB drugs and lasts for several months.

And what alternatives do we have? In Europe, the available anti-TB drug formulations are not suitable for the child patient. Mostly adult tablets are used by breaking them up, which entails a dosage problem.

In the poorest countries, there are fixed-dose dispersible tablets (dispersed in water), adapted to the patient’s weight and with pleasant fruity tastes, which have represented a step forward in the treatment of childhood tuberculosis. However, we do not have syrups that combine the different drugs and that would be especially useful for the little ones.

A contribution from the University of Barcelona

There is no drug on the market that combines, in liquid form and at a fixed dose, the three active ingredients of choice for the treatment of this disease: isoniazid, rifampicin and pyrazinamide. Because? Well, because of the incompatibilities between isoniazid and rifampicin in an aqueous liquid medium. This leads to instability of the active ingredients, their degradation and loss of therapeutic activity.

With these premises and with the social commitment to find an adequate solution for child patients with tuberculosis, the Drug Development Service of the Faculty of Pharmacy and Food Sciences of the University of Barcelona developed a product that overcame the obstacles that the coexistence in a liquid medium of the three reference assets is unfeasible. It obtained a European patent in 2018.

This innovation consists of a liquid formulation, extemporaneously prepared (it is prepared at the moment of taking it) for oral administration, dosable according to the patient’s weight and with a fixed dose of drugs. It has very good palatability (taste, texture and aroma) and does not require the use of water to administer it. In addition, it is stable for five years before reconstitution and for 27 days at refrigerator temperature once reconstituted.

At this point, a logical question arises: why isn’t this product already on the market? The answer is, on the one hand, the lack of funding to complete the final stages of development: conducting clinical trials to validate its usefulness, manufacturing pilot batches, and registering with the health authorities. For that, between 1.5 and 2 years are needed, with a budget of around 800,000 euros.

On the other hand, an industrial partner is needed who wants to register the product with a regulatory agency, assume manufacturing at a competitive price and take care of distribution worldwide. It must be borne in mind that the WHO has expressed its willingness to support the product once it is registered by a regulatory agency.

We can summarize the situation in terms of threats: negative influence of the covid-19 pandemic, lack of economic resources and absence of an industrial partner; and in terms of opportunities: minimum industrialization time, reduced investment and support from the WHO.

Research needs to be promoted

Improving the treatment of childhood tuberculosis is possible, but it is necessary that the control of this old disease be a political priority and that research be promoted.

The University of Barcelona has made a relevant contribution with a liquid formulation that allows doses more adjusted to the weight of child patients and an improvement in treatment. Now, these formulations should reach all affected children in any part of the world, and for this the involvement of powerful entities is necessary. Will it be achieved?

Antoni Soriano-Arandes, from the Infectious Pathology and Pediatric Immunodeficiencies Unit of the Vall d’Hebron University Hospital (Barcelona), has collaborated in the preparation of this article.

Ignacio Madrid Hidalgo, Promoter of the Medicines Development Service (SDM); Department of Pharmaceutical Technology and Physical Chemistry; Faculty of Pharmacy and Food Sciences; University of Barcelona, Barcelona University; Antoni Noguera Julian, Associate Physician and Associate Professor of Pediatrics, Barcelona Universityand Juan A. Cayla Buqueras, President of the Barcelona Tuberculosis Research Unit Foundation, Barcelona Tuberculosis Research Unit (UITB)

This article was originally published on The Conversation. Read the original.