Handling editor: Seye Abimbola
Contributors: MV, JF, RL and GT participated in the writing, reviewing and editing of the article.
Funding: This work was funded in part by the Bill and Melinda Gates Foundation Grants OPP1096734 and OPP1139927, the NIH Grant EB000244, and the MIT Tata Center Grant, NSF Fellowship to MV.
Competing interests: MV, RL and GT are co-inventors on multiple patent applications describing large dose gastric drug delivery systems which can be applied to treating TB: US Patent Applications #62/678,439, #62/678,471 and #62/678,492. RL and GT both report personal fees from Lyndra Inc, outside the submitted work; In addition, RL and GT have a patent PCT/US15-35423 - Residence Structures and Related Methods pending to Lyndra, a patent PCT/US15/35425 - Enteric Elastomers pending to Lyndra, and a patent PCT/US15/35429 - Self-Assembled Residence Devices and Related Methods pending to Lyndra.
Patient consent for publication: Not required.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data sharing statement: No additional data are available.
Tuberculosis (TB), which claims the lives of over 3500 people every day, is the world’s leading killer among infectious diseases.1 According to the WHO, 10 million people developed TB in 2017 with a global economic burden amounting to $12 billion annually.1 2 Furthermore, TB is the most significant pathogen in the global antimicrobial resistance (AMR) crisis.3 Unless radical action is taken, drug-resistant strains of TB will account for 25% of the AMR-related deaths and cost the global economy $16.7 trillion by the year 2050.3 TB treatment is challenging with its prolonged and frequent dosing regimen that may be associated with challenging side effects.4 While significant work has been done to support adherence among people living with TB who are on treatment—including direct observation of therapy and provision of socioeconomic support—there has been limited focus on translation of how the medications themselves and their administration might be altered to improve adherence.
Technologies that enable extended drug release of medication have the potential to overcome patient non-adherence to long and frequent dosing regimens. Long-acting formulations are being implemented for the reduction in the frequency of HIV treatment administration, though they require injections which can be uncomfortable for patients.5 Instead, a long-acting oral dosage would be very attractive and improve adherence to treatment, as the oral route of drug delivery is preferred by patients. Novel ingestible gastric-resident systems for extended controlled drug release are being developed by several groups (including the Langer and Traverso laboratories) for antimalarials and antiretrovirals.6 7
The challenge with designing drug depot systems for TB treatment is to balance the ease and safety of administration with the accommodation of gram-level quantities of TB drugs which have low potency. Under the current regimen during the intensive phase, a 60 kg patient with TB swallows almost 100 g of antibiotics in 1 month.8 One potential area of development which could aid in improved delivery include inhaled or orally delivered nanocarriers which have been designed for extended release of existing TB drugs, although they have yet to be tested in large animal models.9 10 Considering that bedaquiline is the first new approved TB drug in more than 40 years and the dearth of others in the TB drug development pipeline to overcome challenges of the current drugs, nanotechnology can provide an enormous impact with design of novel and targeted delivery systems for existing drugs.11 Ideally, these nanomaterial-based systems would be inexpensive, easy to administer, minimise side effects and reduce the required dosing frequency to improve patient adherence.
Developments in depot systems and more potent drugs can also improve treatment of children, who comprised 1 million (10%) of the new TB cases in 2017.1 Children face challenges in adhering to their treatments due to the difficulty in swallowing pills, bad taste of crushed tablets and aversion to needles.12 Therefore, it is difficult for caregivers to ensure the child is achieving the correct dosage while minimising toxic effects. A recent study in Mozambique found that over 30% of children do not adhere to the WHO recommended regimen.13 Finally, child-friendly first-line TB formulations became available through the Global Drug Facility.12 Optimising second-line drugs for drug-resistant TB in children is much further behind, and there are currently few drug depot systems available to simplify treatment and improve adherence.14 15 Notably, a paediatric dispersible formulation of delaminid may be promising and is currently being assessed in clinical trials.16
TB treatment adherence challenges contribute to poor health outcomes, prolonged infectiousness, drug resistance, relapse and death. While most adherence work has focused on changing the behaviours of people taking TB medications, there has been little work done exploring how the medications might be altered to improve the experience of people living with TB. We challenge global health agencies and funding bodies to prioritise patient-friendly interventions that improve adherence by incentivising more collaborations between clinicians, engineers and patients. These include development of technologies to facilitate dose administration with more potent drugs or novel drug depot systems, while addressing the needs of vulnerable populations such as children. We recognise that preferences and adoption rates for drug delivery modalities, such as inhalable nanotechnology systems, transdermal patches, liquid formulations and gastric resident systems vary across patient groups (table 1). Increased interaction among physicians, engineers and the TB community stands to facilitate innovative solutions to maximise delivery of medicine to patients and transform the treatment of infectious diseases.
