Modeling the Dynamic Relationship Between HIV and the Risk of Drug-Resistant Tuberculosis

Abstract

The emergence of highly drug-resistant tuberculosis (TB) and interactions between TB and HIV epidemics pose serious challenges for TB control. Previous researchers have presented several hypotheses for why HIV-coinfected TB patients may suffer an increased risk of drug-resistant TB compared to other TB patients. Although some studies have found a positive association between an individual’s HIV status and her subsequent risk of multidrug-resistant TB (MDRTB), the observed individual-level relationship between HIV and drug-resistant TB varies substantially among settings. Here, we develop a modeling framework to explore the effect of HIV on the dynamics of drug-resistant TB. The model captures the acquisition of resistance to important classes of TB drugs, imposes fitness costs associated with resistance-conferring mutations, and allows for subsequent restoration of fitness due to compensatory mutations. Despite uncertainty in several key parameters, we demonstrate epidemic behavior that is robust over a range of assumptions. Whereas HIV facilitates the emergence of MDRTB within a community over several decades, HIV-seropositive individuals presenting with TB may, counter-intuitively, be at lower risk of drug resistant TB at early stages of the co-epidemic. This situation arises because many individuals with incident HIV infection will already harbor latent Mycobacterium Tuberculosis infection acquired at an earlier time when drug-resistance was less prevalent. We find that the rise of HIV can increase the prevalence of MDRTB within populations even as it lowers the average fitness of circulating MDRTB strains compared to similar populations unaffected by HIV. Preferential social mixing among individuals with similar HIV-status and lower average CD4 counts among HIV-seropositive individuals further increase the expected burden of MDRTB. This model suggests that the individual-level association between HIV and drug-resistant forms of TB is dynamic and therefore cross-sectional studies that do not report a positive individual-level association will not provide assurance that HIV does not exacerbate the burden of resistant TB in the community.

Antibiotic resistance mechanisms in M. tuberculosis: an update

“…Indeed, drug-resistant M. tuberculosis strains have been circulated mainly among AIDS patients, raising the perspective that resistance might be restricted within that community. However, studies using mathematical modeling, or those carried out with other organisms, first predicted that the fitness cost of drug resistant M. tuberculosis strains could be neutralized by “compensatory mutations,” secondary mutations that correct the fitness to the mutants (Andersson and Hughes 2010; Reynolds 2000; Sergeev et al 2012). In vitro studies later strengthened the hypothesis that drug-resistant M. tuberculosis isolates are able to restore their fitness after prolonged exposure to antibiotics (Gagneux et al 2006; Gillespie et al 2002).…”

Molecular Biology of Drug Resistance in Mycobacterium tuberculosis

“…It has been generally observed that epidemics of drug resistant M. tuberculosis strains mainly circulate among HIV positive patients, raising the hope that these mutants might never spread widely among healthy people. However, first studies using mathematical modeling, as well as those carried out in other organisms, predict that the fitness cost of M. tuberculosis drug resistant strains could be reduced by the subsequent appearance of “compensatory mutations”, i.e., mutations that correct the fitness cost due to earlier mutations (Reynolds 2000; Andersson and Hughes 2010; Sergeev et al 2012). This compensatory evolution restoring fitness of resistant strains might stabilize the epidemic of resistance phenotypes after they emerge.…”

TB incidence and characteristics in the remote gulf province of Papua New Guinea: a prospective study

“…These factors and their impact on TB incidence and outcomes have been well studied in many African countries [2-4]. The incidence of TB in countries with geographically isolated communities such as Papua New Guinea (PNG) is largely unknown and there is very limited data on drug resistance and HIV co-infection in remote PNG communities.…”