Tuberculosis: An Update for the Clinician

Abstract

Tuberculosis (TB) remains a significant global health threat with high mortality and efforts to meet WHO End TB Strategy milestones are off-track. It has become clear that TB is not a dichotomous infection with latent and active forms but presents along a disease spectrum. Subclinical TB plays a larger role in transmission than previously thought. Aerosol studies have shown that undiagnosed TB patients, even with paucibacillary disease, can be highly infectious and significantly contribute to TB spread. Encouraging clinical results have been seen with the M72/AS01_E vaccine. If preliminary results can be confirmed in ongoing larger trials, modelling shows the vaccine can positively impact the epidemic. TB preventive therapy (TPT), especially for high-risk groups like people living with HIV and household contacts of drug-resistant TB patients, has shown efficacy but implementation is resource intensive. Treatment options for infectious patients have grown rapidly. New shorter, all-oral treatment regimens represent a breakthrough, but progress is threatened by rising resistance to bedaquiline. Many new chemical entities are entering clinical trials and raise hopes for all-new regimens that could overcome rising resistance rates to conventional agents. More research is needed on the management of complex cases, such as central nervous system TB and severe HIV-associated TB. Post-TB lung disease (PTLD) is an under-recognised but growing concern, affecting millions of survivors with lasting respiratory impairment and increased mortality. Continued investment in development of TB vaccines and therapeutics, treatment shortening, and management of TB sequelae is critical to combat this ongoing public health challenge.

Keywords: diagnostics; post‐tuberculosis lung disease; prevention; treatment; tuberculosis.

FIGURE 1

Current recommended regimens for TB prevention and treatment. This figure shows regimens that are currently recommended by the World Health Organisation, and in advanced development for tuberculosis (TB) preventive therapy, treatment of drug‐susceptible TB and drug‐resistant TB, respectively. Drugs are colour‐coded by their respective chemical class. *For drug resistant TB patient contacts; **Quinolone susceptibility required and *** Regimens in development within UNITE4TB and PAN‐TB contain novel compounds without cross‐resistance, that could be used as first‐line regimens in individuals with TB disease without prior knowledge of drug resistance profiles. H, isoniazid; P, rifapentine; R, rifampicin; Tx, treatment.

FIGURE 2

Global TB drug pipeline. This figure shows an overview of new therapeutic compounds for TB at different stages of development. From Stop TB Partnership's Working Group on New Drugs [72].

FIGURE 3

Trial schedule for accelerated development of TB treatment regimens. This figure shows a trial schedule illustrating the design of accelerated development of TB treatment regimens in the PAN‐TB and UNITE4TB projects. Regimens that contain combinations of new agents first undergo a 4‐month Phase 2B study to ascertain safety and preliminary efficacy. The best performing regimen enters a duration‐randomisation Phase 2C with clinically relevant endpoints to evaluate further treatment shortening potential based on relapse rates, enabling selection of the best candidates and treatment durations for a Phase 3. Adapted from Hoelscher et al. [76].