Benefits of continuous isoniazid preventive therapy may outweigh resistance risks in a declining tuberculosis/HIV coepidemic

Abstract

Objective Extending the duration of isoniazid preventive therapy (IPT) among people living with HIV (PLHIV) may improve its effectiveness at both the individual and population level, but could also increase selective pressure in favor of isoniazid resistant tuberculosis (TB) strains. The objective of this study was to determine the relative importance of these two effects. Methods Transmission dynamic model Design We created a mathematical model of TB transmission incorporating HIV incidence and treatment, mixed strain latent TB infections, and four different phenotypes of TB drug resistance (pan-susceptible, isoniazid mono-resistant, rifampicin mono-resistant, and multi-drug resistant). We used this model to project the effects of IPT duration on the incidence of isoniazid-sensitive and -resistant TB as well as mortality among PLHIV. We evaluated the sensitivity of our baseline model, which was calibrated to data from Botswana, to different assumptions about the future trajectory of the TB epidemic. Results Our model suggests that, in the context of a declining TB epidemic such as that currently observed in Botswana, the incidence and mortality benefits of continuous IPT for PLHIV are likely to outweigh the potential resistance risks associated with long duration IPT. However, should TB epidemics fail to remain in control, as was observed during the initial emergence of HIV, the selective pressure imposed by widespread use of continuous IPT on isoniazid resistant TB incidence may erode its initial benefits. Conclusions Resistance concerns are likely insufficient to rule out use of continuous IPT when coupled with effective TB treatment, case finding, and HIV control.

Population-level mathematical modeling of antimicrobial resistance: a systematic review

“…Major conclusions include the following: (1) the vast majority of MDR-TB incidence is due to transmitted resistance rather than de novo treatment-related acquisition [30, 39, 40]; (2) to combat resistance, drug susceptibility testing and TB surveillance should be emphasized [41–44]; (3) treatment and drug susceptibility testing should be expanded in community settings in Africa and the private sector in India [42, 43, 45–47]; (4) controlling HIV would help decrease the transmission rates of resistant -TB [48, 49]; (5) isolation or quarantine strategies would help prevent transmission and decrease the number of patients lost to follow-up [50, 51]; and (6) while community-wide intermittent preventative therapy may increase the incidence of drug resistance, the benefits in reducing primary TB infections outweigh the risks. However, such therapy should be coupled with appropriate diagnostic and treatment policies [48, 52–54].…”

TB preventive therapy for people living with HIV: key considerations for scale-up in resource-limited settings

“…Theoretically, asymptomatic disease may be associated with low bacterial burden that can be eradicated by one or two agents and, based on modeling data, the very clear benefits of TPT will likely outweigh a potential risk of drug resistance, especially in countries with a decreasing TB incidence overall (as has been demonstrated where ART coverage has expanded among PLHIV). 19,32–36 Nevertheless, programs should be prepared to conduct active surveillance for resistance to drugs included in their TPT regimens, and also to perform drug susceptibility testing for patients who develop TB disease after receiving TPT.…”

Modelling the HIV-Associated TB Epidemic and the Impact of Interventions Aimed at Epidemic Control

“…IPT was found to be effective at a population-level, but networks with clustering of HIV and TB transmission in intense foci had reduced local impact from IPT due to high rates of TB reinfection. Kunkel et al [103] calibrated a multistrain TB model with HIV to data from Botswana and consider the health benefits and resistance dynamics resulting from continuous IPT for PLHIV. They find health benefits outweigh concerns around increased resistance, so long as sufficient control is maintained for the overall TB epidemic.…”