Advances in the understanding of Mycobacterium tuberculosis transmission in HIV-endemic settings

Abstract

Tuberculosis claims more human lives than any other infectious disease. This alarming epidemic has fuelled the development of novel antimicrobials and diagnostics. However, public health interventions that interrupt transmission have been slow to emerge, particularly in HIV-endemic settings. Transmission of tuberculosis is complex, involving various environmental, bacteriological, and host factors, among which concomitant HIV infection is important. Preventing person-to-person spread is central to halting the epidemic and, consequently, tuberculosis transmission is now being studied with renewed interest. In this Series paper, we review recent advances in the understanding of tuberculosis transmission, from the view of source-case infectiousness, inherent susceptibility of exposed individuals, appending tools for predicting risk of disease progression, the biophysical nature of the contagion, and the environments in which transmission occurs and is sustained in populations. We focus specifically on how HIV infection affects these features with a view to describing novel transmission blocking strategies in HIV-endemic settings.

Figure 1.. Effects of HIV-1 infection on the progression of tuberculosis disease and the transmission window.

Progression to active, pulmonary tuberculosis disease involves a complex sequence of events that is dependent on initial exposure intensity and the interplay between innate and acquired immunity. Thicker arrows represent an enhanced risk and broken arrows indicate poor progression/reversion to the next/preceding phase. Red arrows indicate the sequence in the case of tuberculosis-HIV infection. Most cases of exposure lead to the development of asymptomatic latent tuberculosis infection (LTBI), which is characterized by an immunological response to mycobacterial antigens (using the tuberculin skin test [TST]). This can progress to incipient tuberculosis, which is defined as asymptomatic disease with no radiological or microbiological signs of disease but can be distinguished from LTBI by an immune biomarker progression from infection to disease. Subclinical disease develops thereafter and is classified as asymptomatic disease associated with either radiological or microbiological confirmation of tuberculosis. In some cases, individuals can spontaneously convert their TST to become uninfected again. HIV co-infection alters the dynamics of immune control and can favour progression to infection, in exposed individuals, and/or progression to incipient tuberculosis. It remains unclear if HIV infection increases the risk of becoming infected with LTBI. The risk of progression to active pulmonary tuberculosis can also be substantively enhanced in the presence of HIV co-infection. Conventionally, the transmission window (shown in yellow) has been assumed to circumscribe the development of granulomatous tuberculosis disease, with a high bacterial load and cavities. HIV co-infection can potentially extend this window (shown in pink) by (I) creating a larger proportion of individuals with incipient/subclinical tuberculosis, within whom the propensity to transmit is as yet unclear (II) creating a larger pool of actively diseased individuals who can transmit and (III) presenting poor treatment outcomes due to extra-pulmonary tuberculosis and drug-drug interactions.