Transmission of drug-resistant tuberculosis in HIV-endemic settings

Abstract

The emergence and expansion of the multidrug-resistant tuberculosis epidemic is a threat to the global control of tuberculosis. Multidrug-resistant tuberculosis is the result of the selection of resistance-conferring mutations during inadequate antituberculosis treatment. However, HIV has a profound effect on the natural history of tuberculosis, manifesting in an increased rate of disease progression, leading to increased transmission and amplification of multidrug-resistant tuberculosis. Interventions specific to HIV-endemic areas are urgently needed to block tuberculosis transmission. These interventions should include a combination of rapid molecular diagnostics and improved chemotherapy to shorten the duration of infectiousness, implementation of infection control measures, and active screening of multidrug-resistant tuberculosis contacts, with prophylactic regimens for individuals without evidence of disease. Development and improvement of the efficacy of interventions will require a greater understanding of the factors affecting the transmission of multidrug-resistant tuberculosis in HIV-endemic settings, including population-based molecular epidemiology studies. In this Series article, we review what we know about the transmission of multidrug-resistant tuberculosis in settings with high burdens of HIV and define the research priorities required to develop more effective interventions, to diminish ongoing transmission and the amplification of drug resistance.

Figure 1:. Overview of the transmission dynamics of drug-resistant tuberculosis and the effects of HIV (evidence-based or theoretical) at each step of the cycle

(A) Acquired resistance (due to suboptimal adherence, decreased drug concentrations, or drug-drug interactions). (B) Transmission of drug-resistant M tuberculosis. (C) Establishment of drug-resistant M tuberculosis infection. (D) Progression from recently acquired or latent infection to active disease. (E) Superinfection or reinfection with drug-resistant M tuberculosis. *Contact can be an uninfected healthy contact, contact with latent infection (drug-susceptible or drug-resistant tuberculosis), or contact with active disease (drug-susceptible or drug-resistant tuberculosis).

Figure2:. New approaches for studying the transmission dynamics of drug-resistant tuberculosis

(A) A hypothetical heat map illustrating the probability of all possible infector-infected associations estimated. The method used to generate this heat map (TransPairs) estimates the probability and direction of transmission occurring between all possible pairs of patients based on a timed phylogenetic tree. In the example presented here there are five patients (a, b, c, d, e) who can either be an infector or an infected patient relative to the other patients. Patient b is the most likely infector of patients a and c, whereas patient a probably infected patient d. Patient e was most likely infected by patient a, but could also have been infected by patient b. In this group of patients, b is identified as the index case, with no high-probability infector identified for this case. (B) Transmission modelling output can also be represented phylogenetically as high-likelihood transmission chains (TransPhylo). Stars show predicted transmission events followed by a change in branch colour, indicating transmission from one patient to the next. Importantly, TransPhylo can also infer unsampled cases, but performs best if the sampling density is high. (C) The time of infection for each patient is among the parameters estimated by TransPhylo. The time difference between estimated infection time and the time of diagnosis can serve as an estimate of the speed of disease progression. The plot illustrates a scenario where a hypothetical factor used to stratify patients into two groups (represented by the pink and purple graphs) affects the speed of disease progression.