Community-Wide Isoniazid Preventive Therapy Drives Drug-Resistant Tuberculosis: A Model-Based Analysis

Community-wide isoniazid preventive therapy may lead to long-term rises in resistance at the population level. A Deeper Look at Drug Resistance Although some things may seem obvious at first glance, looking in more depth may paint a different picture. In some complex situations, asking questions in different ways may lead to very different answers. One example is the use of isoniazid preventive therapy (IPT) for tuberculosis (TB) in HIV-prevalent communities. Because HIV-infected individuals are much more likely to develop TB than immunocompetent people, the World Health Organization has recommended the use of IPT in HIV-infected individuals that are symptom-free for TB co-infection. The use of IPT has raised the specter of drug resistance; however, to date, studies have not observed an increase in drug-resistant TB in individuals on IPT. Now, Mills et al. use mathematical modeling to show that even if IPT does not increase drug resistance in infected individuals, community-wide IPT can drive increases in drug resistance at the population level. The authors developed mathematical models to identify the conditions under which community-wide IPT could increase the burden of drug-resistant TB. They found that community-wide IPT increases selective suppression of drug-sensitive infection, thus indirectly conferring an advantage to drug-resistant strains. These data should be considered when determining policy for preventive therapy. Tuberculosis (TB) control is especially difficult in settings of high HIV prevalence; HIV co-infection erodes host immunity and increases risk of progression to active TB. Studies have demonstrated that a 6-month (or longer) course of monotherapy with isoniazid [isoniazid preventive therapy (IPT)] can reduce this risk. The World Health Organization endorses IPT for symptom-free individuals with HIV/TB co-infection and has recommended expanding IPT to entire communities (community-wide IPT). Although previous reviews have not found a statistically significant elevated risk of isoniazid-resistant TB among individuals previously treated with IPT, community-wide IPT programs may nonetheless generate substantial selective pressure and increase the burden of drug-resistant TB (DRTB). We developed mathematical models to identify the conditions under which community-wide IPT interventions could increase the burden of isoniazid-resistant Mycobacterium tuberculosis, even when we assumed that IPT does not select for resistance among those treated with IPT. We found that in models that included any mechanism of interstrain competition (such as partial immunity conferred by a previous M. tuberculosis infection), community-wide IPT interventions conferred an indirect benefit to drug-resistant strains through selective suppression of drug-sensitive infections. This result suggests that the absence of an observed elevation in the risk of DRTB among those receiving IPT in small-scale studies of limited duration does not imply that the selective pressure imposed by community-wide IPT will not be substantial. Community-wide IPT may play an important role in TB control in these settings, and its rollout should be accompanied by interventions to detect and treat drug-resistant disease.