Research Article: Inclusion of key populations in clinical trials of new antituberculosis treatments: Current barriers and recommendations for pregnant and lactating women, children, and HIV-infected persons

Date Published: August 15, 2019

Publisher: Public Library of Science

Author(s): Amita Gupta, Michael D. Hughes, Anthony J. Garcia-Prats, Katherine McIntire, Anneke C. Hesseling

Abstract: Amita Gupta and colleagues discuss priorities in clinical research aimed at improving tuberculosis prevention and treatment in pregnant women, children, and people with HIV.

Partial Text: Globally, 10 million cases of active tuberculosis (TB) disease and 1.6 million TB-related deaths occurred in 2017 [1]. Pregnant and postpartum women, children < 15 years old, and HIV-infected persons account for 20% of the global TB burden, with an estimated 216,000, 1,000,000, and 1,040,000 cases each year, respectively [1,2]. Special considerations in these populations include TB disease spectrum and severity, lower diagnostic sensitivity, possible differential treatment responses, drug dosing and interactions, and challenges in acquiring high-quality data through clinical trials [3–5]. Without clear consideration of actual risks and benefits of trial participation, pregnant women have been uniformly excluded from TB therapeutic trials, especially for multidrug-resistant (MDR) TB [6,7], based on fears of harming the fetus and legal liability [8]. Children have better treatment outcomes than adults for most forms of TB, but they present different pharmacologic responses to drugs and typically require higher mg/kg doses, especially if very young [9–11]. HIV-infected persons experience complicated drug–drug interactions (DDIs) and worse TB treatment outcomes than HIV-uninfected persons and have 2–3 times greater likelihood of TB-related mortality [12]. In March 2018, the World Health Organization (WHO) held a technical consultation focused on advancing clinical trial design for more successful development of new TB treatments [13], including enrollment of key populations that may be currently underrepresented in clinical trials. Although many such populations exist, including migrants, prisoners, homeless people, and healthcare workers, the technical consultation discussions were concentrated on three populations and were framed around five questions (Box 1). This review is part of a Collection, “Advances in Clinical Trial Design for the Development of New TB Treatments: A Call for Innovation,” and highlights key aspects, barriers, and potential solutions to conducting TB therapeutic clinical trials in pregnant and lactating women, children, and HIV-infected persons [14]. TB therapeutic trials that exclude key populations are often not followed by trials in those populations. Pregnant and lactating women, children, and HIV-infected persons contribute a large proportion of the global TB burden and require optimized TB treatment and access to the latest therapeutic advances. Overall, adequate inclusion and appropriate study of these populations remain problematic, particularly for pregnant and lactating women; some advances are being made for children, yet pediatric TB trials lag far behind adult trials despite the potential for better TB treatment outcomes among children, and further evaluation of DDIs is needed in HIV–TB-coinfected populations to ensure that HIV-infected persons, particularly those with more advanced HIV disease, more fully benefit from therapeutic advances. Importantly, despite the differences among these populations, several cross-cutting themes exist and can serve as a way forward toward inclusion of key populations in TB clinical trials (Box 2). Source:


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