In the light of the outcry of the high pill burden, severe toxicity and high treatment non-adherence rates, and many more challenges associated with the treatment of TB, in particular of multidrug-resistant tuberculosis (MDR-TB), innovative drug therapies are beginning to be explored. One of them - inhaled TB drugs - were presented at the 46th Union World Conference on Lung Health held recently in Cape Town.
Professor Anthony Hickey, a Senior Research Pharmacologist at RTI International Research Triangle Park, was of the opinion that inhaled drug therapy for TB should not be approached with any fear and the duration to get it to commercial production should not be too long, considering that it is not, and will not, be an entirely new and blind search for effective options.
There is a history of inhalation therapy in the late 1940s when the streptomycin drug started showing signs of resistance. The inhalation therapy was however abandoned only to resurface in the 1980s in trials for HIV drugs until 2010 when tobramyanin was rolled out. But then, after this, it seems the trail died again,even though there were indications of effective responses. Needless to say, there is already a model to follow for researchers, as outlined by this history on inhaled therapies, from the stages of formulation of the drug, dosage development, device development for administration, and the steps towards product approval. These were the sentiments shared by Professor Anthony Hickey.
It has been noted already that oral or injectable drug therapy are probably the cheaper way to administer TB drugs. However, it is also evident that these approaches have not been the most favorite among patients and even health care professionals. Inhalation therapies may actually be more expensive to take to the ordinary person but as shared by Dr Stefano Giovagnoli, Assistant Professor in Pharmaceutical Sciences at the University of Perugia, Italy, there are great health benefits that the inhaled therapy brings.
Firstly, for lung delivery there can be cellular targeting in high concentration of TB bacilli. This may possibly rapidly reduce transmission of the TB bacilli due to high airway concentration of drug delivery. Secondly, there will be lower systemic exposure, thus minimizing side effects, especially like damage to the liver, since the drugs will be administered directly to the lungs. Thirdly, inhaled dosages can be easily manipulated to be lower or higher as needed. This means that dosage can be easily adjusted in case of children and adults, as well as for prophylactic doses. Lastly, there can be systemic onset of action, thereby accelerating high surface area for absorption.
The advantages of inhaled drug therapy could be endless. It would accentuate other health benefits and long term research and management of TB. Unlike injections, inhalers are non-invasive and also eliminate needle based risks of cross infection, especially for patients with HIV and hepatitis; and eliminate the pain associated with injectables for MDR-TB treatment, especially in underweight adults and children.
This will also open up opportunities to reduce the duration of treatment in both drug susceptible and drug resistant TB. It is also likely to result in better treatment compliance versus injectables and/or oral therapy.
Inhalers are easy to store and transport without refrigeration. They are easier to administer as compared to injections and thereby reduce the work burden on the resource strapped and understaffed health delivery systems. This would be especially advantageous in high burden and resource limited settings. Lastly and most importantly, the inhalation therapy has the potential to use existing treatment regimens that are already approved by the WHO to have anti-mycobacterial activity, but which cannot be given systematically due to high toxicity.
Professor Bernard Fourie, Professor in Medical Microbiology at the University of Pretoria, with the help of others, has already initiated consultations with the parties that will engage with the end product. He shared that in establishing whether health care staff and patients are ready for inhaled anti-TB drugs, over 92% of patients noted that they would be comfortable using an inhaler and 84% found it easy to use, with indications that it will help in administration of medication in elderly patients too.
Although there are no major foreseeable barriers (medical or cultural) to this product adoption, 22% respondents did voice concerns about durability in repeated use of the inhaler and 26% queried about the safety and hygiene of the procedure.however, let us not forget that patients with asthma have used inhalers for a very long time now and certainly with the similarities, lessons can be drawn to ensure safety and hygiene in case of anti TB inhalers.
Areas to consider in the inhaled drug therapy for TB would be:
- Prophylactic inhalers for high risk populations, including persons working in active TB hot spots, for treatment of latent TB rather than wait for active TB development. Low dosage drugs introduced in the airway may target quick absorption and minimal toxicity.
- Investigation of lung toxicity and airway sensitivity as a conduit for potentially toxic and high dose TB drugs.
- Positive impact of the therapy on the high rate of comorbidities that TB has and its linkages with other conditions like HIV, diabetes, smoking, etc. Already, these conditions have some drugs that adversely interact with TB drugs and if not, they add to the toxicity and pill burden.
- Inter-tracheal administration of TB medication may only offer protection for pulmonary TB and not extra-pulmonary TB.
Smart phones have eliminated the need for calculators, physical fitness gadgets, mobile radio, computers, camera, scanner, voice recorder and even currency converter machines. If we could harness the human development advancement in technology, we could advance a step further in case of TB treatment by exploring the use of inhaled therapies and stop the TB epidemic in our generation. The journey will be worth it. As Charles Darwin had noted, "it is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change".
(Alice Tembe is CNS Special Correspondent from Swaziland)