Last week, Dr. Kaiser shared his thoughts and perspectives as a medical doctor on the current state of TB drug regimens. This week he shares specific ideas on how TB drug R&D could be improved.
From a clinical perspective, I think there are some less obvious aims to optimize that can similarly yield a big clinical payoff:
- Increasing bacteriocidality against non-dividing organisms. While there are ample agents that can kill dividing TB, and some that are bacteriostatic to non-dividing cells, a regimen particularly targetted at optimizing the bacteriocidal attack on non-dividing organisms would yield unique benefits for TB treatment. First, it would help to reduce resistance by limiting selection pressure: organisms would be unlikely to survive even a single agent, even if they were not actively replicating, and multiple simultaneous agents could work synergistically and help to clear monoresistant isolates before their resistance progressed. Second, it could help to reduce the treatment burden of latent disease, by specifically targetting quiescent bacteria; this in turn would have clear benefits for reducing active cases later. Third, such a focused regimen could assist in optimizing intermittent treatment regimens by reducing treatment time and the chance of treatment failure, which in turn offers the chance to reduce the sizeable cost of DOT. Tuberculosis’ natural propensity for rapid resistance makes a single-agent regimen probably impossible for active disease, but a focused highly bacteriocidal dual drug regimen may be possible with the right compounds.
- Extending half-lives of active metabolites. As I mentioned above, this has especial benefit for intermittent dosing administration, which helps to reduce the cost involved in patient contact for DOT, but it also has an obvious effect on specifically improving treatment adherence and reducing failure. For migrant populations or other high-risk cohorts where patient contact is at best spotty or difficult, even reducing contacts merely to weekly could dramatically improve clearance rates by enabling the patient contact we do have to be more effective, which in turn reduces spread and infectivity and increases cure. Similarly, a highly motivated patient that is nevertheless inaccessible due to distance or hazardous environment could be given long-duration packets when proper DOT contact is intermittent or impossible — valuable for us when we have patients in higher altitudes where snow and ice frequently close the highway. A metabolite that remains active longer in turn translates into greater flexibility, and flexibility with DOT is always an advantage by reducing the impact of individual missed doses and improving our ability to reach the patient.
- Reducing drug-drug interactions. Apart from the hepatotoxicity risk of the standard HREZ regimen, potent P450 inducers such as rifampin cause unexpected treatment complications. Diabetic regimens require adjustment (and poorly controlled diabetics are likely to become the most clinically significant patient cohort at risk for relapse or failure), seizure medications often need to be increased and more frequently monitored, and more than a few women on oral contraceptives have had unexpected pregnancies while on treatment. Not only are these events upsetting or dangerous for the patient, but they add significant additional complexity to visits and put additional load on both treating physicians and PCPs. For many patients with little or no access to regular health care, visits with the TB physician may be their only MD contacts with any consistency, and TB is already complicated enough without the treatment for their TB upending management of their other chronic health issues.
Clearly, progress against tuberculosis proceeds slowly, both due to a public in the developed world with the misconception that TB is a conquered evil, and a disproportionate disease impact in impoverished regions where access and technological development are much less. But even in the developed world, with a global and increasingly mobile population, the spectre of drug-resistant tuberculosis on a grand scale should terrify us all. By correctly, effectively and promptly treating tuberculosis, we can greatly reduce what will certainly be a future and more intractable epidemic. More to the point, however, we can reduce the impact of that treatment so that we really can bring “normalcy” back to our patients promptly just as we do regularly for many other communicable diseases. In my treatment role, I look forward to new advances that offer me the chance to get my patients quickly back to where they were. For both the demon of resistant disease and the constant assault of latent and active disease, the development of new tuberculosis drugs is vital to finally eradicating this notorious illness once and for all.
Cameron Kaiser, MD is the medical consultant for tuberculosis for the Riverside County Department of Public Health in southern California. This essay reflects his views and not necessarily those of the department or the county. He can be reached at firstname.lastname@example.org.
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