Rethinking tuberculosis control by targeting previously treated individuals

Tuberculosis is now the leading cause of death due an infectious disease.1WHOGlobal Tuberculosis Report 2017. World Health Organization, Geneva2017Google Scholar Urgent action with new approaches is needed to achieve WHO's elimination targets of an 80% reduction in tuberculosis cases and a 90% reduction in deaths by 2030.1WHOGlobal Tuberculosis Report 2017. World Health Organization, Geneva2017Google Scholar Marx and colleagues2Marx FM Floyd S Ayles H Godfrey-Faussett P Beyers N Cohen T High burden of prevalent tuberculosis among previously treated people in Southern Africa suggests potential for targeted control interventions.Eur Respir J. 2016; 48: 1227-1230Crossref PubMed Scopus (27) Google Scholar previously identified that, in high tuberculosis burden communities in sub-Saharan Africa, individuals who have previously been treated for tuberculosis have as much as a 5 times increased risk of a repeat tuberculosis disease episode compared with individuals without a history of tuberculosis treatment. Furthermore, the investigators noted that previous tuberculosis treatment was reported in 18·5% of prevalent tuberculosis cases. These findings were restricted to HIV-uninfected adults; the difference in risk based on previous tuberculosis episode was not significant in individuals with HIV. These findings suggest that HIV-uninfected individuals previously treated for tuberculosis are a potential focus for a targeted approach in tuberculosis disease prevention. In The Lancet Global Health, Florian Marx and colleagues3Marx FM Yaesoubi R Menzies NA et al.Tuberculosis control interventions targeted to previously treated people in a high-incidence setting: a modelling study.Lancet Glob Health. 2018; (published online Feb 19.)http://dx.doi.org/10.1016/S2214-109X(18)30022-6Summary Full Text Full Text PDF PubMed Scopus (28) Google Scholar investigate the effect of two control strategies directed at previously treated individuals in a suburb of Cape Town, South Africa—a setting with high tuberculosis recurrence rates and low HIV co-prevalence. The team modelled two interventions: active case finding among previously treated cases alone and the active case finding paired with life-long isoniazid preventive therapy following treatment completion of the initial tuberculosis episode. The researchers found that combining these two interventions could achieve a 40% reduction in incidence and a 41% reduction in tuberculosis deaths over 10 years. The benefit of such targeted interventions can be separated into two components: avoiding recurrence and improving early identification of tuberculosis disease in previously treated individuals (which contributes to a roughly 30% reduction in incidence) and preventing new infections attributable to transmission from those cases (which contributes a further 10% reduction in incidence). Predicting the effect of targeted interventions in other settings using a modelling approach requires detailed knowledge of local transmission and epidemiology. The investigators showed that, with similar assumptions and a force of infection cut in half, targeting previously treated cases can avert a third of incident disease. For other settings, an estimate of the direct effect can be calculated using the proportion of recurrent tuberculosis cases, often measured using molecular epidemiological data.4Uys PW van Helden PD Hargrove JW Tuberculosis reinfection rate as a proportion of total infection rate correlates with the logarithm of the incidence rate: a mathematical model.J R Soc Interface. 2009; 6: 11-15Crossref PubMed Scopus (41) Google Scholar The indirect effect can be estimated using the fraction of recurrent cases combined with their relative risk of transmission.5Brooks-Pollock E Danon L Defining the population attributable fraction for infectious diseases.Int J Epidemiol. 2017; 46: 976-982Crossref PubMed Scopus (13) Google Scholar Here, for example, previously treated cases were assumed to be 1·5 times more likely to transmit tuberculosis than treatment-naive cases. The population-level effects of targeting previously treated cases are compelling. As Marx and colleagues outline, this is a group of individuals who have engaged with the medical system and can be traced through those services. However, several individual-level issues should be considered. First, the reason that previously treated tuberculosis cases contribute such a high proportion of incident disease could lead to modification of the intervention. If inherent host factors drive the increased susceptibility to disease progression, then lifelong prophylaxis might be reasonable to protect them. However, if increased risk is due to immunological defects that improve over time, a more time-limited prophylaxis is more appropriate.6Uys P Brand H Warren R van der Spuy G Hoal EG van Helden PD The risk of tuberculosis reinfection soon after cure of a first disease episode is extremely high in a hyperendemic community.PLoS One. 2015; 10: e0144487Crossref PubMed Scopus (15) Google Scholar Second, recognition that isoniazid is not easily tolerated over long periods because of liver toxicity is important.7Saukkonen JJ Cohn DL Jasmer RM et al.An official ATS statement: hepatotoxicity of antituberculosis therapy.Am J Respir Crit Care Med. 2006; 174: 935-952Crossref PubMed Scopus (843) Google Scholar Individuals are instructed to avoid acetaminophen and alcohol while on isoniazid; to ask for such lifelong modifications would benefit from quantifying an individual-level benefit in addition to that for the community. Finally, the anticipation of being able to capture 90% of the previously treated population and maintain them on isoniazid therapy for a median of 6 years is optimistic. Others have reported that patients with tuberculosis are often quite mobile, especially after completing care, and that even during care, dropout rates are high (conservatively 9% in the Western Cape Province from which the model cohort resides).8Dudley L Mukinda F Dyers R Marais F Sissolak D Mind the gap! Risk factors for poor continuity of care of tuberculosis patients discharged from a hospital in the Western Cape, South Africa.PLoS One. 2018; 13: e0190258Crossref PubMed Scopus (12) Google Scholar Implementation of isoniazid preventive care for individuals with HIV has had variable uptake.9Akolo C Bada F Okpokoro E et al.Debunking the myths perpetuating low implementation of isoniazid preventive therapy amongst human immunodeficiency virus-infected persons.World J Virol. 2015; 4: 105-112Crossref PubMed Google Scholar Additionally, the stigma of having had a tuberculosis diagnosis is prevalent, so consideration of tagging a group of individuals over a long period with having this diagnosis might not be desirable without addressing such stigma as well.10Daftary A Frick M Venkatesan N Pai M Fighting tuberculosis stigma: we need to apply lessons learnt from HIV activism.BMJ Glob Health. 2017; 2: e000515Crossref PubMed Scopus (44) Google Scholar We are encouraged by the modelling of this novel approach by Marx and colleagues ahead of consideration of how to successfully develop an intervention study. For real progress to be made in tuberculosis control, innovative-targeted approaches will be necessary to successfully reduce disease rates, balancing individual and community level benefits. We declare no competing interests. Tuberculosis control interventions targeted to previously treated people in a high-incidence setting: a modelling studyIn this high-incidence setting, the use of targeted active case finding in combination with secondary isoniazid preventive therapy in previously treated individuals could accelerate decreases in tuberculosis morbidity and mortality. Studies to measure cost and resource implications are needed to establish the feasibility of this type of targeted approach for improving tuberculosis control in settings with high tuberculosis and HIV prevalence. Full-Text PDF Open Access