In this study, we used a calibrated population-based mathematical model to project the effect of two types of interventions targeted to previously treated people in a tuberculosis high-incidence setting. Our data suggest that, if targeted active case finding and secondary isoniazid preventive therapy were introduced to complement existing tuberculosis control efforts in this setting, the burden of tuberculosis could be substantially reduced. Our study supports the idea that efforts for prevention and prompt detection of recurrent tuberculosis35x35Harries, AD, Chimzizi, RB, Nyirenda, TE, van Gorkom, J, and Salaniponi, FM. Preventing recurrent tuberculosis in high HIV-prevalent areas in sub-Saharan Africa: what are the options for tuberculosis control programmes?. Int J Tuberc Lung Dis. 2003;
PubMed | Google ScholarSee all References could offer novel opportunities for tuberculosis control in settings of high tuberculosis incidence.
We propose these targeted control interventions during a time when untargeted efforts, such as population-wide enhanced case finding and household-based screening8x8Ayles, H, Muyoyeta, M, Du Toit, E et al. Effect of household and community interventions on the burden of tuberculosis in southern Africa: the ZAMSTAR community-randomised trial. Lancet. 2013;
Summary | Full Text | Full Text PDF | PubMed | Scopus (71) | Google ScholarSee all References and mass isoniazid preventive therapy9x9Churchyard, GJ, Fielding, KL, Lewis, JJ et al. A trial of mass isoniazid preventive therapy for tuberculosis control. N Engl J Med. 2014;
Crossref | PubMed | Scopus (85) | Google ScholarSee all References have yielded insufficient evidence of effect, and where novel approaches are urgently needed to reduce the burden of tuberculosis in communities most affected by the disease. Targeting control efforts to groups at high risk of tuberculosis could enable health services to make more efficient use of available resources. In many high tuberculosis prevalence settings, previously treated people can be easily identified and experience an elevated risk of tuberculosis,16x16Marx, FM, Floyd, S, Ayles, H, Godfrey-Faussett, P, Beyers, N, and Cohen, T. High burden of prevalent tuberculosis among previously treated people in Southern Africa suggests potential for targeted control interventions. Eur Respir J. 2016;
Crossref | PubMed | Scopus (1) | Google ScholarSee all References therefore they might be an attractive target for focused interventions.
We project that within 10 years in this setting, a combination of targeted active case finding and secondary isoniazid preventive therapy could avert more than a third of incident tuberculosis cases and tuberculosis deaths. Targeted active case finding alone could have a notable effect on tuberculosis prevalence and mortality, but is expected to have a smaller effect on incidence; our simulations suggest that a marked effect of targeted active case finding is achieved when it can be coupled with secondary isoniazid preventive therapy. Our projections show that much of the effect of targeted active case finding and secondary isoniazid preventive therapy accrues in the first few years after their implementation. The diminishing effect over time suggests a saturation effect, which might imply that such targeted interventions could be used within an adaptive control strategy.21x21Yaesoubi, R and Cohen, T. Identifying dynamic tuberculosis case-finding policies for HIV/tuberculosis coepidemics. Proc Natl Acad Sci USA. 2013;
Crossref | PubMed | Scopus (8) | Google ScholarSee all References
Our study constitutes a first step towards better understanding the effect of interventions targeted to previously treated people in high-incidence settings. However, several limitations must be noted. We applied our model to a specific setting with a high tuberculosis incidence and where high rates of recurrent tuberculosis due to relapse and re-infection had been previously reported.12x12Verver, S, Warren, RM, Beyers, N et al. Rate of reinfection tuberculosis after successful treatment is higher than rate of new tuberculosis. Am J Respir Crit Care Med. 2005;
Crossref | PubMed | Scopus (233) | Google ScholarSee all References,14x14Marx, FM, Dunbar, R, Enarson, DA et al. The temporal dynamics of relapse and reinfection tuberculosis after successful treatment: a retrospective cohort study. Clin Infect Dis. 2014;
Crossref | PubMed | Scopus (31) | Google ScholarSee all References,36x36van Rie, A, Warren, R, Richardson, M et al. Exogenous reinfection as a cause of recurrent tuberculosis after curative treatment. N Engl J Med. 1999;
Crossref | PubMed | Scopus (455) | Google ScholarSee all References We note that the effect of interventions targeted at previously treated people, which we project for this setting, might not be easily generalised to other high-incidence settings for several reasons. High rates of recurrent tuberculosis have been reported from several other high-incidence settings.10x10Panjabi, R, Comstock, GW, and Golub, JE. Recurrent tuberculosis and its risk factors: adequately treated patients are still at high risk. Int J Tuberc Lung Dis. 2007;
PubMed | Google ScholarSee all References,11x11Sonnenberg, P, Murray, J, Glynn, JR, Shearer, S, Kambashi, B, and Godfrey-Faussett, P. HIV-1 and recurrence, relapse, and reinfection of tuberculosis after cure: a cohort study in South African mineworkers. Lancet. 2001;
Summary | Full Text | Full Text PDF | PubMed | Scopus (291) | Google ScholarSee all References,13x13Glynn, JR, Murray, J, Bester, A, Nelson, G, Shearer, S, and Sonnenberg, P. High rates of recurrence in HIV-infected and HIV-uninfected patients with tuberculosis. J Infect Dis. 2010;
Crossref | PubMed | Scopus (41) | Google ScholarSee all References However, the population-level effect of targeted interventions will also depend on the size of the target group and their contribution to tuberculosis transmission in the population. In this particular setting, persistently high rates of incident tuberculosis have generated a large subgroup of people who had previously been treated for tuberculosis (about 10% of all adults) and who constitute a substantial proportion of the prevalent tuberculosis burden in the population (about 30% of prevalent cases).
Although our projections are consistent with the epidemiology of tuberculosis in other high-incidence communities in South Africa,5x5Claassens, M, van Schalkwyk, C, den Haan, L et al. High prevalence of tuberculosis and insufficient case detection in two communities in the Western Cape, South Africa. PLoS One. 2013;
Crossref | PubMed | Scopus (13) | Google ScholarSee all References,16x16Marx, FM, Floyd, S, Ayles, H, Godfrey-Faussett, P, Beyers, N, and Cohen, T. High burden of prevalent tuberculosis among previously treated people in Southern Africa suggests potential for targeted control interventions. Eur Respir J. 2016;
Crossref | PubMed | Scopus (1) | Google ScholarSee all References we expect interventions among previously treated people to be less effective in settings with lower tuberculosis incidence, and where a smaller proportion of the tuberculosis burden is attributable to former tuberculosis patients. For example, previously treated people accounted for 4·1% of the adult population and for 13% of prevalent tuberculosis cases in Lusaka, Zambia,6x6Ayles, H, Schaap, A, Nota, A et al. Prevalence of tuberculosis, HIV and respiratory symptoms in two Zambian communities: implications for tuberculosis control in the era of HIV. PLoS One. 2009;
Crossref | PubMed | Scopus (78) | Google ScholarSee all References and for 1·5% and 15%, respectively, in Nigeria37x37First National tuberculosis Prevalence Survey 2012, Nigeria (Report). National Tuberculosis Control programme of the Federal Ministry of Health. See: www.who.int/tb/publications/NigeriaReport_WEB_NEW.pdf. ()
Google ScholarSee all References—two settings with lower tuberculosis incidence than our study setting. Nonetheless, given that new approaches for tuberculosis control are most needed in areas where tuberculosis incidence has been persistently high, our results suggest that efforts to both prevent and rapidly detect and treat recurrent disease will produce important health benefits. In our scenario analysis, for which we lowered the force of infection by 50%, we noted that targeted active case finding in combination with secondary isoniazid preventive therapy reduced the expected number of incident tuberculosis cases and deaths to a lesser extent, but still averted a third of incident cases.
Differences in the prevalence of HIV in a population might influence the effect of interventions targeted to previously treated people in several ways. Communities with higher HIV prevalence might experience more recurrent tuberculosis given the elevated risk of re-infection with tuberculosis among HIV-infected individuals,38x38Daley, CL, Small, PM, Schecter, GF et al. An outbreak of tuberculosis with accelerated progression among persons infected with the human immunodeficiency virus. An analysis using restriction-fragment-length polymorphisms. N Engl J Med. 1992;
Crossref | PubMed | Google ScholarSee all References and thus benefit more from similar interventions. Survival after a first tuberculosis episode might be reduced among those not on ART; those on ART may be subject to more regular clinical follow-up that would limit the benefit of additional case finding interventions in this group.
The population-level effect of targeted active case finding and secondary isoniazid preventive therapy will be dependent upon existing patterns of passive health-care seeking behaviour. In settings where there are longer delays to diagnosis, additional interventions to more rapidly identify and treat recurrent cases would be more effectual, whereas in areas where individuals self-present quickly after onset of symptoms, we would expect more modest returns from investment in combined targeted active case finding and secondary isoniazid preventive therapy interventions. This is consistent with our sensitivity analysis, which showed that the time to passive tuberculosis detection among treatment-experienced adults correlated with the projected effect.
Uncertainty around parameters of the natural history of tuberculosis, particularly those determining re-infection, disease progression, and mortality among previously treated individuals, leads to substantial uncertainty in the modelled outcomes. To avoid bias towards higher estimates of effect, we used conservative prior ranges of parameters for treatment-experienced adults, similar to those among treatment-naive adults. Specifically, we did not enforce higher susceptibility, lower partial immunity, or higher disease progression risk among those with a history of previous tuberculosis, but did allow posterior parameter values derived from calibration to vary by treatment history. While posterior distributions of our model are consistent with treatment-experienced people being more likely to become productively re-infected than treatment-naive people, we did not explicitly model differential risk of exposure, which could also be a mechanism driving increased risk of recurrent disease.39x39Cohen, T, Colijn, C, Finklea, B, and Murray, M. Exogenous re-infection and the dynamics of tuberculosis epidemics: local effects in a network model of transmission. J R Soc Interface. 2007;
Crossref | PubMed | Scopus (65) | Google ScholarSee all References
Our study is further limited by uncertainty around the efficacy of secondary isoniazid preventive therapy towards preventing recurrent tuberculosis. As shown in our sensitivity analysis, higher effects of secondary isoniazid preventive therapy would result in higher effect at the population level. Only two studies—a randomised trial30x30Fitzgerald, DW, Desvarieux, M, Severe, P, Joseph, P, Johnson, WD Jr, and Pape, JW. Effect of post-treatment isoniazid on prevention of recurrent tuberculosis in HIV-1-infected individuals: a randomised trial. Lancet. 2000;
Summary | Full Text | Full Text PDF | PubMed | Google ScholarSee all References and a cohort study31x31Churchyard, GJ, Fielding, K, Charalambous, S et al. Efficacy of secondary isoniazid preventive therapy among HIV-infected Southern Africans: time to change policy?. AIDS. 2003;
Crossref | PubMed | Scopus (87) | Google ScholarSee all References—have assessed the effect of preventive therapy on recurrent tuberculosis. Both were limited in size and focused on people living with HIV. More available data from the field would improve our projections.
We used a simple mathematical model that does not enable us to explore specific intervention designs or consider many practical issues related to implementation. In particular, in our main analysis we assumed that interventions could be aggressively rolled out in these suburban settings—ie, that individuals with previous treatment could be effectively identified, enrolled, and screened for tuberculosis on average every 12 months, that 90% could be enrolled in secondary isoniazid preventive therapy upon completing treatment, and 15% would drop out from secondary isoniazid preventive therapy every year. Although we believe high coverage levels of the interventions could be achieved in this relatively small suburban setting, the effect of these interventions would clearly be lower if interventions were less vigorously applied or if some individuals were not reachable by the intervention.
In conclusion, our study provides impetus for further research to better understand the individual and population-level benefits of tuberculosis control interventions targeted at previously treated people. Studies and trials of the feasibility, safety, effect, and population-level effect of targeted active case finding and secondary isoniazid preventive therapy in previously treated people in high-incidence settings would be particularly useful. Other interventions to prevent recurrent tuberculosis such as adjuvant immunotherapy during tuberculosis treatment,40x40Wallis, RS. Reconsidering adjuvant immunotherapy for tuberculosis. Clin Infect Dis. 2005;
Crossref | PubMed | Scopus (88) | Google ScholarSee all References extending the duration of tuberculosis treatment for certain high-risk patients,34x34Wu, J, Dhingra, R, Gambhir, M, and Remais, JV. Sensitivity analysis of infectious disease models: methods, advances and their application. J R Soc Interface. 2013;
Crossref | PubMed | Google ScholarSee all References or post-treatment vaccination might be considered in the future. Further mathematical modelling, in which detailed costs of interventions are also included, would be useful for policy makers as they could establish whether such interventions are cost-effective and how investment in these approaches may compare with alternatives.