Beneficial and perverse effects of isoniazid preventive therapy for latent tuberculosis infection in HIV-tuberculosis coinfected populations

Abstract

In sub-Saharan Africa, where the emergence of HIV has caused dramatic increases in tuberculosis (TB) case notifications, new strategies for TB control are necessary. Isoniazid preventive therapy (IPT) for HIV-TB coinfected individuals reduces the reactivation of latent Mycobacterium tuberculosis infections and is being evaluated as a potential community-wide strategy for improving TB control. We developed a mathematical model of TB/HIV coepidemics to examine the impact of community-wide implementation of IPT for TB-HIV coinfected individuals on the dynamics of drug-sensitive and -resistant TB epidemics. We found that community-wide IPT will reduce the incidence of TB in the short-term but may also speed the emergence of drug-resistant TB. We conclude that community-wide IPT in areas of emerging HIV and drug-resistant TB should be coupled with diagnostic and treatment policies designed to identify and effectively treat the increasing proportion of patients with drug-resistant TB.

Fig. 1.

Condensed model structure. The full model consists of two parallel models (one for HIV-infected and one for HIV-uninfected) that have structures similar to the one depicted here. Individuals move from one submodel to the other when they are infected with HIV. The full model structure can be found in Supporting Text. Green compartments represent infection/disease with a drug-sensitive M. tuberculosis strain; red compartments represent infection/disease with either a fit or unfit drug-resistant strain; the yellow compartment represents infection with two strains (i.e., drug-sensitive and fit/unfit drug-resistant or unfit and fit drug-resistant). Each of the compartments summarizes a number of distinct infection/disease states. The latent infection compartments include individuals who can progress to TB disease either slowly or rapidly or who can be reinfected with another strain of circulating M. tuberculosis. The TB disease compartments include those who have active (infectious) disease and extrapulmonary (noninfectious) disease. Individuals with TB disease may self-cure (contain their infection and return to latency) or, if they have active disease and are detected and treated, they may recover from disease. Those who are treated for drug-sensitive TB may acquire drug resistance. Individuals in all compartments (with the exception of those with TB disease) may be reinfected by circulating strains of M. tuberculosis (dotted arrows). IPT works by clearing drug-sensitive organisms from latently infected individuals (red arrows).

Fig. 2.

Effects of IPT. Varying coverage of IPT (blue = 0% coverage, green = 33% coverage, orange = 66% coverage, and red = 99% coverage). (a) TB prevalence (per 100,000) by years since IPT was introduced. (b) Proportion of TB that is drug-resistant by years since IPT was introduced. (c) HIV-associated deaths (per 1,000) by years since IPT was introduced. (d) IPT selective pressure. Increasing IPT coverage can cause a “phase change” from the coexistence of drug-sensitive and -resistant strains to dominance of the drug-resistant strains. Here the relative fitness of the most fit drug-resistant strains were assumed to be only 70% of the fitness of the drug-sensitive strains.

Fig. 3.

Adjuncts to improve the performance of preventive therapy for latent TB infection. Comparison of using drugs that treat latent resistant infections (dashed lines) versus improving treatment of resistant TB disease (solid lines) in addition to baseline IPT coverage (blue = 0% coverage, green = 33% coverage, orange = 66% coverage, and red = 99% coverage). (a) TB prevalence (per 100,000) by years since the policy was introduced. (b) Proportion of TB that is drug-resistant by years since the policy was introduced. (c) HIV-associated deaths (per 1,000) by years since the policy was introduced.