Adherence and Acquired Drug-Resistance in Tuberculosis: Wisdom Stood on its Head

Drug-resistant tuberculosis is an important public health problem. 1 Erratic adherence to antituberculosis treatment often results in treatment failure and is widely considered to be the driving force behind the emergence of drug-resistance in previously treated patients."Drugs do not work in patients who do not take them," once said by C. Everett Koop, the former (1982-89) US Surgeon General. 2 It is a statement that rings true -perhaps universally across disease paradigms.We know for sure that it is particularly true for the diseases, such as human immunodeficiency virus (HIV) infection where empirical evidence shows that even minor degrees of non-adherence lead to sub-optimal treatment outcomes. 3,4The same belief applies to the treatment of tuberculosis (TB) as well.Mitchison propounded four mechanistic principles that explain the emergence of acquired drug-resistance as a result of non-adherence to treatment. 5Simultaneously, Lipsitch and Levin 6 described a mathematical model that predicted that non-adherence and heterogeneity of susceptibility are important determinants of acquired drug-resistance in TB.Many of us might even think that the assertion that poor adherence results in drug-resistance does not need empirical verification.Indeed, it seems to be an obvious fact.But, things do not remain the same for long in science.Once a while someone appears on the scene declaring that it is the earth that revolves around the sun, not the other way around.In that sense, the Copernicus seems to have arrived in the field of TB.Recently, Gumbo and Colleagues at the University of Texas Southwestern Medical Center reported that the emergence of drug-resistance in TB is the result of pharmacokinetic variability among patients rather than non-adherence. 7They used a novel in vitro pharmacodynamic model, the hollow fiber system, to study the effect of varying levels of non-adherence on bactericidal and sterilising activities of TB treatment.And, to everyone's surprise, they reported that missing up to 60% of daily doses made no difference to ultimate treatment success as well as the emergence of acquired drug-resistance. 7They did not stop with that; of late, they have come up with empirical evidence to show that fast acetylators of isoniazid have a significantly higher risk of treatment failure and acquired drug-resistance despite supervised drug administration. 8The later findings do not exonerate non-adherence as the cause of drugresistance; instead, they draw our attention to interpatient variation in bio-availability, a hitherto overlooked factor.