Assessing the public health impact of tolerance-based therapies with mathematical models

Disease tolerance is a defense strategy against infections that aims at maintaining host health even at high pathogen replication or load. Tolerance mechanisms are currently intensively studied with the long-term goal of exploiting them therapeutically. Because tolerance-based treatment imposes less selective pressure on the pathogen it has been hypothesised to be “evolution-proof”. However, the primary public health goal is to reduce the incidence and mortality associated with a disease. From this perspective, tolerance-based treatment bears the risk of increasing the prevalence of the disease, which may lead to increased mortality. We assessed the promise of tolerance-based treatment strategies using mathematical models. Conventional treatment was implemented as an increased recovery rate, while tolerance-based treatment was assumed to reduce the disease-related mortality of infected hosts without affecting recovery. We investigated the endemic phase of two types of infections: acute and chronic. Additionally, we considered the effect of pathogen resistance against conventional treatment. We show that, for low coverage of tolerance-based treatment, chronic infections can cause even more deaths than without treatment. Overall, we found that conventional treatment always outperforms tolerance-based treatment, even when we allow the emergence of pathogen resistance. Our results cast doubt on the potential benefit of tolerance-based over conventional treatment. Any clinical application of tolerance-based treatment of infectious diseases has to consider the associated detrimental epidemiological feedback.Author summary: Conventional therapies improve patient health by eliminating the pathogen, or, at least, reducing its burden. Recently, alternative therapies that exploit host tolerance mechanisms have received attention from the medical community as a promising strategy. These treatments aim at reducing the level of illness due to the infection, rather than eliminating the pathogen directly. Using a mathematical model, we show that although these treatments are beneficial at the individual level, they can have undesired public health consequences. In particular we show that tolerance-based treatment gives more time for the disease to spread in the population, which in turn increase its prevalence. Moreover, in the case of a low coverage of the treatment of a chronic infection, the overall mortality can increase.