Understanding latent tuberculosis: the key to improved diagnostic and novel treatment strategies

Abstract

Treatment of latent tuberculosis (LTBI) is a vital component of tuberculosis elimination but is not efficiently implemented with available diagnostics and therapeutics. The tuberculin skin test and interferon gamma release assays can inform that infection has occurred but do not prove that it persists. Treatment of LTBI with isoniazid targets actively replicating bacilli but not non-replicating populations, prolonging treatment duration. Developing more predictive diagnostic tests and treatments of shorter duration requires a greater understanding of the biology of latent tuberculosis, from both host and bacillary perspectives. In this article we discuss the basis of current diagnosis and treatment of LTBI and review recent developments in understanding the biology of latency that may enable future improved diagnostic and treatment strategies.

Ability of preventive therapy to cure latent Mycobacterium tuberculosis infection in HIV-infected individuals in high-burden settings

“…Isoniazid's main activity is bactericidal, highly effective against actively replicating bacteria (30, 31), but unlikely to completely cure a LTBI with few replicating bacteria (29). In vitro and mouse studies have shown that rifampicin and rifapentine can sterilize (31,32) and would therefore be expected to more often result in a cure of LTBI.…”

“…It has been suggested that ART, perhaps through immune reconstitution, would increase the proportion of latent infections cured by isoniazid (7,29). A recent pragmatic randomized controlled trial in South Africa examined the additional impact of IPT in patients already receiving ART (39).…”

“…Historical data on HIVnegative populations have suggested a long-term protective effect lasting years after completion of a 6-9 mo course of IPT (27,28), suggesting that cure was achieved. However, the short interval between therapy completion and TB disease has led to speculation that reactivation of noncured infections was responsible for some of the posttherapy disease episodes occurring in trials in HIVpositive populations (7,29). Our results are also consistent with the recently published findings of the Thibela study, whose authors conclude that "reactivation of inadequately treated latent tuberculosis infection" was one factor which may have contributed to the lack of effect on TB incidence in their trial of mass IPT (9), and provide additional evidence that noncure is the underlying mechanism.…”

Immunological Signatures Identifying Different Stages of Latent Mycobacterium tuberculosis Infection and Discriminating Latent from Active Tuberculosis in Humans

“…However, several recent evidences support the notion that LTBI is not a single defined state but comprises a heterogeneous and dynamic spectrum of interaction patterns between host and pathogen [8]. This heterogeneity may lead to different outcomes, ranging from clearing the infection to pre-reactivation of the disease, probably reflecting various states of bacterial behaviour between dormancy and steady state replication [8][9][10][11].…”

“…The WHO recommends systematic screening of contacts of TB patients and high-risk groups in order to achieve the post 2015 tuberculosis strategy aiming to reduce the tuberculosis incidence by 90% by 2035 compared with the 2015 incidence [6]. Improving diagnostic tools of LTBI is therefore urgently needed [7,8], and more research should be done to identify biomarkers able to predict the progression from LTBI to active TB disease.…”