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Sci Transl Med. Author manuscript; available in PMC 2014 April 10.
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Sci Transl Med. 2013 April 10; 5(180): 180ra49. doi:10.1126/scitranslmed.3005260.
Community-wide isoniazid preventive therapy drives drug-

resistant tuberculosis: a model-based analysis
HL Mills1, T Cohen2, and C Colijn3
1Bristol Centre for Complexity Sciences, University of Bristol, Bristol, UK
2Center for Communicable Disease Dynamics, Department of Epidemiology, Harvard School of

Public Health, MA, USA
2Division of Global Health Equity, Brigham and Women’s Hospital, Boston, MA, USA
3Department of Mathematics, Imperial College, London, UK
Abstract
Tuberculosis control has proven especially difficult in settings of high HIV prevalence as HIV co-
infection erodes host immunity and leads to a high risk of progression to active tuberculosis.
Studies have demonstrated that a 6-month (or longer) course of monotherapy with isoniazid
(isoniazid preventative therapy (IPT)) can reduce this risk of progression. The World Health
Organization endorses the use of IPT for symptom-free individuals with HIV/tuberculosis co-
infection and has placed considerable effort in expanding IPT to entire communities (community-
wide IPT). Though previous reviews have not found a statistically significant elevated risk of
isoniazid-resistant tuberculosis among those previously treated with IPT, community-wide IPT
programs may nonetheless generate substantial selective pressure and increase the burden of drug-
resistant TB (DRTB). We develop mathematical models to identify the conditions under which
community-wide IPT interventions can increase the burden of isoniazid-resistant M. tuberculosis,
even when IPT does not select for resistance among those treated with IPT. In any model that
explicitly or implicitly includes forms of inter-strain competition (such as partial immunity
conferred by a previous M. tuberculosis infection), community-wide IPT interventions confer an
indirect benefit to drug-resistant strains through selective suppression of drug-sensitive infections.
We demonstrate that aggressive community-wide IPT can have an impressive impact on
reductions of drug-sensitive disease, but at the cost of increasing the selective pressure for
resistance. Improving the detection and treatment of DRTB can mitigate this risk. The lack of an
observed elevation in the risk of DRTB among those receiving IPT in small-scale studies of
limited duration does not imply that the selective pressure imposed by community-wide IPT will
not be substantial. Community-wide IPT programs will likely play an important role in disease
control in high incidence settings and their roll-out should be accompanied by interventions for the
detection and treatment of drug-resistant disease.
Introduction
WHO guidelines recommend that HIV infected individuals free of symptoms suggestive of
tuberculosis receive treatment with isoniazid preventive therapy (IPT) for at least 6 months
[1]. The rationale for this recommendation is that individuals with HIV are at high risk of
Author contributions
HLM, TC and CC designed the model. HLM wrote and ran the model. HLM, TC and CC analysed the results and wrote the paper.
Competing interests
The authors declare no competing interests.
Mills et al. Page 2
progression to active tuberculosis disease (TB) if infected with M. tuberculosis [2] and
multiple studies have documented that IPT reduces the risk of progression to disease among
HIV-infected individuals with positive tuberculin skin tests [3]. Despite this strong WHO
recommendation, uptake of IPT has been slow with only 178,000 HIV positive individuals
receiving IPT in 2010 [4].
While there are many explanations for the delayed scale-up of IPT, one persistently
documented concern is that widespread use of IPT may lead to an increasing burden of
isoniazid-resistant TB in communities [1]. Given the importance of isoniazid to the efficacy
of first-line regimens [5, 6] and the potential that isoniazid-resistance may serve as a
stepping-stone to combination resistance (such as multi-drug resistance), understanding the
potential for community-wide IPT to increase levels of drug resistant TB (DRTB) is critical.
During the development of the WHO IPT guidelines, a formal review process was
undertaken to assess whether IPT can increase the risk of developing DRTB. This review,
conducted according to Grading of Recommendations Assessment, Development and
Evaluation (GRADE) criteria, included eight studies and a meta-analysis [7]. The summary
measure of relative risk of isoniazid resistant TB among those that had previously received
IPT compared to those that had not received IPT was 1.87 (95% Confidence Interval [0.65–
5.38]). Based on what was judged to be “moderate quality of evidence” the committee made
a “strong recommendation” that IPT does not increase the risk of developing DRTB [1].
In this paper, we address the question of whether and how community-wide IPT policies can
increase levels of DRTB from a different perspective than the one taken in the GRADE
evaluation. The studies included in the GRADE evaluation assess only the direct effect of
IPT on the risk of isoniazid-resistant disease among those receiving this intervention.
However, because TB is a transmissible disease, we should also consider potential indirect
effects of such large-scale interventions. It is possible for IPT to select for resistance at the
population level even if it does not cause acquired resistance to isoniazid among those
treated (i.e. no direct effect). Here we use mathematical models to demonstrate how this
might occur and to identify the assumptions needed to confidently conclude that
community-wide IPT interventions would not increase the levels of isoniazid resistant TB in
populations with high HIV prevalence.
There are three mechanisms by which community-wide IPT could theoretically cause
increasing levels of DRTB in a population:
1. Failure to detect active TB in an individual before starting IPT can lead to acquired
resistance (mutations occur which cause resistance and these are selected due to
inadvertent monotherapy during active disease) [8, 9, 10, 11].
2. Use of IPT during latency may select for sporadically occurring isoniazid-resistant
mutants and hence increase the risk of DRTB among those treated [12, 13].
3. Community-wide use of IPT may confer a competitive advantage to circulating
strains of isoniazid-resistant M. tuberculosis strains by exerting selective pressure
against isoniazid-susceptible strains.
While the first and second mechanisms are very important to consider, in this paper we
focus on elucidating the conditions under which the third mechanism might occur. Whether
selective suppression of isoniazid-susceptible strains through community-wide IPT would
facilitate higher levels of DRTB depends on how strains of M. tuberculosis compete within
and between human hosts. The degree to which strains confer partial immunity to
superinfection and/or progression [14, 15, 16, 17] and the specific mechanisms by which
strains compete are not yet well understood. Accordingly, we have constructed mathematical
Mills et al. Page 3
models that allow us to evaluate how varying the mechanisms and strength of inter-strain
competition affects the projected impact of community-wide IPT on the short and longer-
term levels of TB and isoniazid-resistant TB in populations where HIV is highly prevalent.
By focusing our analysis on this third mechanism, we can identify whether, under optimal
conditions where we target IPT appropriately (only giving IPT to HIV infected individuals
without active TB, thereby averting mechanism 1) and do not generate resistance through
acquisition (averting mechanism 2), community-wide IPT interventions could still present a
strong enough selective pressure to increase the expected burden of INH-resistance.
Results
To determine how inter-strain competition affects the impact of community-wide IPT we
use a deterministic model of HIV and TB transmission with two phenotypes of TB: drug
sensitive and drug resistant (Figure 1). TB infection is modelled with latent and active
classes for each strain and mixed latent classes, as in previous models [18]. HIV infection is
represented with an SI model, only a fraction of the population are at risk of HIV infection
(as in [19]). We parameterize the model to generate epidemics that qualitatively reflect the
trajectories and magnitude of HIV and TB trends in Lesotho, a country with a high burden
of both diseases, and thus where large community-wide IPT interventions might be deployed
(see Table S2 for the parameters). We simulate IPT when the epidemics are stable and
compare the drug resistant and drug sensitive incidence and prevalence 20 and 100 years
after IPT, in models with and without the IPT intervention.
Community-wide IPT interventions have counteracting effects in our simulations. IPT acts
to suppress DSTB but may facilitate the emergence of DRTB solely through the selective
suppression of drug-sensitive strains. Figure 2 shows the prevalence of latent infection and
incidence of active disease with DSTB and DRTB in the presence and absence of the
community-wide IPT interventions. For these simulations, parameter values are set to their
baseline values (parameters shown in Table S2). Note that while the expected short-term
increase in DRTB over the 10 years after IPT is introduced is minimal, the long-term effect
is more pronounced. As we increase the selective pressure of the community IPT
intervention (i.e. when the rate of getting placed on IPT (tHIV) is high and the duration of a
course of IPT (1/w) is long), we observe much larger short- and longer-term decreases in the
incidence of DSTB, but at the expense of increasing the incidence of DRTB (see Figure 3).
The degree to which IPT can increase the levels of drug-resistant infection and disease
depends on both the mechanism and strength of inter-strain competition. When there is a
low degree of protection conferred by previous infection (low immunity, high values of k
and kHIV) we observe more re-infection, and hence more ‘theft’ of latently infected
individuals from one strain to another. This occurs through both fast and slow progression.
The effect through slow progression is mediated by the fraction of individuals (d) in whom
the initial infecting strain remains dominant after re-infection. Weaker immunity also results
in more mixed infections. When immunity is low, the two strains are not only competing for
susceptible hosts, but are also competing for latently infected hosts. The rapid effects of
competition through the fast progression mechanism suggests that changing the magnitude
of the immunity term (k) will have a strong early effect and a less dramatic late effect
(compare Figure 4A&C).
As lower levels of immunity lead to higher expected numbers of individuals in the mixed
infection states, high values of k may allow for community-wide IPT interventions to have a
stronger resistance-promoting effect through the selective action of IPT against drug-
sensitive bacilli within individuals with mixed latent infections. However, this effect of IPT
is mitigated when superinfection events are less likely to lead to a change in the dominant
Mills et al. Page 4
strain (i.e. when d is high). The increased tendency of an infection to remain the dominant
strain after re-infection with another strain (high values of d and dHIV) shifts the focus of
inter-strain competition towards fully susceptible hosts. In contrast to variations in partial
immunity (k), the effect of changes in d are more modest in the short term and greater in the
long term because it takes time for competition via susceptible hosts to play out (Figure
4B&D).
An effective increase in the number of available hosts arises in two ways in all TB models
that incorporate interactions between two or more TB strains. The first is that individuals
exposed to one strain of TB retain some partial immunity protecting them from re-infection,
and hence ultimately from progression and active TB disease with the other strain. If the
prevalence of one strain is reduced, then the number of hosts with protective immunity is
reduced. Depending on whether immunity is specific or not, this can effectively raise the
number of hosts susceptible to (re-)infection with the other strain. The second is that when
individuals are re-infected, models assume that they enter either a latent or active state of
infection with the re-infecting strain. This means that re-infection replaces some or all of the
risk of progression with the first strain with risk of progression with the newly-infecting
strain.
We conducted uncertainty and sensitivity analyses of the model using parameter sets
selected by Latin hypercube sampling (LHS). While there was substantial variation in
outcomes, all LHS parameters sets resulted in predicted levels of DRTB that were higher in
scenarios with IPT. The sensitivity analysis revealed that the partial immunity term, kHIV, is
most correlated with DRTB, implying that reducing our degree of uncertainty about this
parameter is most critical for establishing the impact of IPT. Further details are in the
Supplementary Material.
In the model results presented up to this point, we assumed optimal program conditions in
which individuals with active TB were not inadvertently prescribed monotherapy and also
that treatment of active TB does not generate acquired resistance. Relaxing the strong
assumption that treatment of active TB does not generate new resistance through acquisition
reveals that over ranges of reasonable risk of acquired resistance, the long term effect of
selective pressure of community-wide IPT on the emergence of DRTB remains (Figure 5).
Over shorter time periods, when the risk of acquired resistance during treatment is quite high
(≈10%, see Figure 5 where blue solid line dips below blue dotted line), the beneficial effect
of preventing cases of latent infection from progressing to active TB can outweigh the
selective pressure of IPT. This implies that in programs where treatment of active DSTB
tends to generate substantial DRTB, prevention of progression from latency may initially
mitigate the emergence of DRTB, but this effect may be reversed over longer time horizons
as the selective pressure of community-wide IPT takes effect.
To confirm that our results are governed by inter-strain competition, we developed a model
in which the strains do not compete with each other (see Fig. S6). This requires not only that
there not be immunity (an unrealistic assumption for TB [17]), but also that re-infection not
alter the risk of progression or disease with an existing infection. In this case, community-
wide IPT reduces drug-sensitive disease without increasing resistance levels. Figure 6 shows
the prevalence and incidence of latent and active DSTB and DRTB in a model without
competition and illustrates the striking difference between these results and those of the
competition model (Figure 2). However, if immunity is re-introduced into the model (or if
we assume that individuals with mixed infection do not experience a doubled rate of slow
progression to disease) the resistance-promoting effect of community-wide IPT returns.
Mills et al. Page 5
Discussion
There is a compelling argument that IPT should not cause acquired resistance among
eligible individuals receiving appropriate treatment. Latent infection has been considered a
state characterized by relatively low bacterial levels and relative physiologic inactivity of the
bacteria that are present. Based on previous estimates of mutation rates conferring resistance
to isoniazid (on the order of 10−8 mutation per bacterium per generation [20]), the risk of
selecting for resistant mutants during latency should be low [21].
However, more recently, TB researchers have proposed a model of latency that suggests that
latent infection is a continuous spectrum of disease states characterized by heterogeneous
bacterial populations in different physiological states [22]. Others investigations have found
that bacterial division [12] and mutation [13] may occur quite commonly during states that
would be clinically characterized as latency. These studies collectively suggest that use of
monotherapy during latency could result in acquired resistance. However, the data
summarized during the GRADE review for the 2011 WHO IPT guidelines [1] did not find a
statistically significant increased risk of isoniazid-resistant disease among patients
previously treated with IPT; this was interpreted as an absence of evidence that IPT causes
acquired resistance to isoniazid. While it is encouraging that this systematic review did not
detect a statistically significant effect, it should be noted that the point estimate is consistent
with a greater than 80% increased risk and that only an extremely large study (or group of
studies) of IPT would be capable of detecting a statistically significant effect.
The implementation of community-wide IPT interventions requires that health care workers
can rule out active disease among HIV-seropositive patients. Screening tools with good
operating characteristics have been published [23], but in some settings these screening tools
alone may not be adequate to rule out subclinical TB disease [8, 24, 9, 10, 11]. There is
therefore a risk that as IPT interventions are rolled out in new settings, isoniazid resistance
might arise as a result of inadvertent treatment of active disease with a single agent.
While it is possible that IPT can cause resistance among those with latent infection, and
resistance is likely to occur among those with active TB that improperly receive IPT, in this
paper, we developed models that assume that IPT does not lead to resistance through either
of these direct mechanisms. Instead, we explored whether IPT could affect resistance levels
indirectly through inter-strain competition. Accordingly, the assumptions of our model are
consistent with data such as those reported in [25], in which the risk of isoniazid resistance
among those receiving IPT was no greater than the baseline levels in the community, within
the 2.5 years of the study. Our results indicate that an increased risk of DRTB need not
occur among individuals receiving IPT in the short term in order for IPT to present a risk of
driving resistance through population-level inter-strain competition. The fact that isoniazid-
resistant disease is already prevalent in most settings where IPT would be implemented
increases the relevance of this investigation [26]. We also note that even though in our
model we assume that IPT does not cause acquired resistance, it allows individuals with
either latent susceptible or latent mixed susceptible and resistant infections to clear only
their sensitive isolates; in observational studies this effect of IPT would not be
distinguishable from true acquired resistance and thus may explain some of the (non-
statistically significant) increased risk in the GRADE evaluation.
It is possible to develop multi-strain TB models that assume that strains do not compete for
hosts through competition either for latently infected or susceptible hosts (see Fig. S6).
Without competition, infection with one strain does not affect the risk of infection (ie no
partial immunity) or progression with the other. The latter requires mixed infection states
where the total progression rate is the sum of the progression rates of the two strains. In such
Mills et al. Page 6
a system, IPT given to mixed latently infected individuals would select for resistant bacilli
when given to individuals with mixed infections. This effect would be stronger than in the
model we have used because without partial immunity there would be more of these
individuals. Paradoxically, when strains are not competing, the relative risk of progression to
drug-resistant compared to drug-sensitive disease would be increased for individuals
receiving IPT (because some of them would harbour mixed infections) but selectively
treating drug-sensitive infections would not drive resistance (as shown in Figure 6).
However, if strains are in competition for hosts and the number of mixed infections is low,
an increased individual-level risk of DRTB among those given IPT would not be detected,
because the increases in DRTB due to the combination of competition and a reduction of
DSTB would not occur among the treated individuals, but rather would occur in the
population at large. Therefore, individual-level studies that do not show increased risk of
DRTB among those given IPT should not be taken to imply that community-wide IPT will
not have long-term population level consequences. We emphasize that the assumptions
needed for a model without inter-strain competition are not consistent with current
understanding of TB. For example, there is ample evidence for partial immunity conferred
by previous infection [17]. However, developing a model that is devoid of competition
between resistant and sensitive strains is the only way in which we could fully remove the
population-level effect of IPT on the spread of resistance.
While it is clear that human hosts can harbor multiple M. tuberculosis strains [27, 28, 29, 30,
31], little is known about how these strains interact [32, 33, 34]. The consequences of such
forms of within-host interaction can have important impacts on TB epidemiology and drug-
resistance in particular [35]. As shown in our uncertainty analysis, the protection conferred
by previous infection and the interaction of strains in the mixed latent classes can have a
large impact on the balance of DSTB and DRTB strains in the population. We believe that
currently collected epidemiological data can currently provide only limited information
about the mechanisms and magnitude of interstrain competition. In most populations, the
fraction of M. tuberculosis isolates that is typed is low and the time course over which the
effects of strain competition are expected to manifest is long. While these practical issues
challenge the use of routinely collected data to inform our understanding of interstrain
competition, the introduction of whole genome sequencing as a routine typing tool will
permit the development and application of genomic approaches for identifying the effects of
this type of competition from M. tuberculosis sequences collected from communities. In the
meantime, we believe that animal models may serve as a very useful tool for investigating
the effects of previous M. tuberculosis exposure on subsequent infection or risk of
progression. These types of in vivo studies, in which model organisms can be exposed to
particular M. tuberculosis simultaneously or in sequence [33, 34, 36], can provide key
information about competition effects, though the generalizability of these findings to
humans will remain in question. Further in vivo studies of inter-strain competition are
needed to improve our understanding of these interactions and their dependence on host
immune type and strain type in order to predict the effects of interventions such as
community-wide IPT.
Wargo and colleagues reported that in a mixed strain (drug-sensitive and drug-resistant)
rodent malaria model selective removal of drug-sensitive parasites through chemotherapy
resulted in “competitive release” of the previously constrained drug-resistant parasites [37],
giving within-host densities of drug-resistant parasites above the level observed in the
absence of the drug-sensitive competitor. Consistent with this, Harrington and colleagues
found that preventative intermittent treatment of malaria in pregnant women with
sulfadoxine-pyrimethamine was associated with a higher fraction of cases with a resistance
allele and increased levels of parasitemia [38]. Whether similar mechanisms apply to M.
tuberculosis is not known.
Mills et al. Page 7
Recently, Basu et al [39] used a model to predict the effects of IPT. Their model assumes
strong competition between DRTB and DSTB that occurs both because of partial immunity
and because they assume re-infection results in strain replacement. Their approach to
modeling the selective effect of IPT was quite conservative and consequently only showed
small benefits of IPT and a relatively small increase in DRTB over 50 years. The role that
IPT plays in the emergence of resistance results from the combined effect of the individual-
level and population-level effects we have outlined. We anticipate that under scenarios in
which IPT has a larger benefit in their model, it will also cause increased resistance due to
the population-level effects we report here.
Our model makes simplifying assumptions that limit our ability to predict the impact of
community-wide IPT on the future trajectory of the TB epidemic. We considered a simple
model of HIV infection with two states (infected/not infected) and our IPT intervention and
treatment strategies were modelled in a simple way. Furthermore, in focusing the effects of
competition in the absence of direct effects of IPT interventions (mechanisms 1 and 2 of the
introduction) we have not modelled the acquisition of drug resistance among those with
latent drug-sensitive infections. We have not aimed to use the model for quantitive
prediction of the effects of IPT for these reasons. Rather we have focused our investigation
on the mechanisms by which community-wide IPT may accelerate the spread of DRTB even
within perfectly operating programs.
Our analyses demonstrate that community-wide IPT can be an effective intervention against
DSTB in settings of high HIV prevalence, but this intervention can also increase the
absolute burden of DRTB. We expect that the most aggressive IPT programs will produce
the greatest selective pressure for drug-resistant strains that are already circulating in these
communities. We therefore emphasize the crucial role of conducting surveillance for DRTB,
especially as community-wide IPT programs go to scale. Our simulations indicate that the
rate at which we expect IPT to drive up drug resistance is fairly slow, so there should be
ample opportunity to introduce universal drug susceptibility testing to ensure that patients
receive effective therapy for drug-resistant disease. Ensuring access to rapid testing and
treatment for drug-resistant disease should mitigate unintended consequences of community-
wide IPT.
As new TB drugs are introduced to the market [40], the opportunity to use these drugs as
monotherapy among contacts of individuals with highly drug-resistant disease has been
suggested [41]. While this approach may well help protect those at risk of developing
disease with very difficult (or nearly impossible) to treat disease, it also may risk driving up
the burden of disease resistant to these newest agents. Ideally, we would have enough new
agents to reserve some for use as prevention and others for treatment of active disease.
Materials and Methods

We use a deterministic model of TB and HIV transmission with two phenotypes of TB:
drug-sensitive (DSTB) and drug-resistant (DRTB). The TB model structure is similar to
previous models (see flowchart in Figure 1): after infection with M. tuberculosis, individuals
remain latently infected (LSi or LRi) or rapidly progress to active TB disease (ISi or IRi).
Latently infected individuals may slowly progress to active TB disease and, whilst latent,
can be re-infected by strains of TB circulating in the community. We assume partial
immunity for those latently infected [14, 15, 16, 17]; for simplicity we assume that this
immunity acts to reduce the rate at which previously-infected individuals are successfully
re-infected upon re-exposure. Individuals who are re-infected can either progress rapidly to
active disease with the superinfecting strain, or can retain both infections and suffer a slow
rate of progression to active disease characterized by whichever strain is dominant (LSRi and
Mills et al. Page 8
LRSi) (as in Cohen et al. [18]). We refer to states of latency where an individual harbors
infection with both types of strains as “mixed strain infections” [27, 28, 29, 30]. IPT given
to individuals with mixed strain infections will efficiently select for isoniazid resistant
bacilli resulting in a resistant latent infection.
We repeat this core TB model structure for three types of individuals indexed by HIV status
(as in [19]): 1) individuals possessing behavioral or social characteristics that mean that they
are not at risk of HIV infection; 2) those at risk of HIV, but as yet uninfected; and 3) those
with HIV infection. We indicate HIV status within TB infection model states with the use of
subscript i. In the model, we assume that HIV infection increases the risk of rapid
progression to TB after infection, the reactivation of latent infections, as well as mortality. A
complete model description, equations, parameters and implementation details are in the
Supplementary Material.
We parameterize the model to generate epidemics that qualitatively reflect the trajectories
and magnitude of HIV and TB trends in Lesotho, a country with a high burden of both
diseases, and thus where large community-wide IPT interventions might be deployed (see
the Supplementary Material). We introduce IPT in the model when the prevalence of active
TB is approximately 475/100,000 and the prevalence of HIV is approximately 28%.
During IPT individuals may become infected with DRTB but not DSTB. Figure 1B shows
details of how the IPT intervention is modeled. We explore the effect of increasing the rate
that individuals receive IPT and the duration of the course of IPT on both the DSTB and the
DRTB epidemic.
Competition between DSTB and DRTB arises in two ways in this model. The first relates to
immunity: individuals with latent TB infection retain partial immunity that reduces their risk
of re-infection with either strain of TB. When interventions act preferentially against one
strain, its force of infection is expected to decrease. This results in an increased availability
of susceptible hosts who may be infected by the competing strain. We assume that partial
immunity is lower for individuals infected with HIV (kHIV) and individuals who have had a
TB infection and been treated with treated with IPT retain some partial immunity (kIPT).
The second form of competition relates to how multiple strains interact within a host. In the
model, a proportion of individuals with a latent infection who are re-infected will progress
rapidly to active infection with the newly infecting strain. Of those that do not, a fraction d
move to a mixed latent class with their original strain remaining dominant while the
remainder (1−d) move to a mixed latent class with the new strain becoming dominant. Each
is at risk of progression with the dominant strain only (but remain at risk from subsequent
reinfection). We assume that individuals with mixed latent infection have the same
progression rates as latently infected hosts harboring only a single strain. Accordingly, re-
infection with a new strain effectively substitutes a portion of risk of progression with the
original strain with a similar risk of progression with the new strain. Higher values of d
reflect more competition in the model at the level of susceptible hosts, since with higher d,
re-infected individuals retain risk of slow progression with their original infection, reducing
each strains’ ability to compete for latent hosts.
Overall, competition between strains in the model is mediated by the parameters d, dHIV, k
and kHIV. We explore the effects of changes in these parameters, keeping other variables
fixed at baseline values. We assume dHIV = d and .
We show time trends and report the effects of IPT at 20 and 100 years after the initiation of
this intervention. We have assumed that the operational characteristics of tuberculosis
treatment programs do not change over the course of these simulations. While this is
Mills et al. Page 9
unrealistic (e.g. new diagnostics, drugs, vaccines and treatment approaches will likely
become available), this approach allows us to to provide qualitative insight into the potential
early and late effects of community-wide IPT on drug-susceptible and DRTB. We compare
trends in the incidence of active DRTB and the prevalence of latent drug-resistant infections
in the presence and absence of community-wide IPT. Since many of the values of
parameters are not known or easily measured, we conduct uncertainty and sensitivity
analyses using a latin hypercube sampling (LHS) approach. Further details of the LHS are
provided in the Supplementary Material.
In addition to our main modeling results, we have also developed an alternative model
structure in which the two strains of TB do not compete with one another (we refer to this as
the non-competing model, see Fig. S6)). In a model without competition, an increase in
either strain should not have any explicit or implicit effect on the duration of latency, risk of
progression, or duration of infectiousness of the other strain. In the Discussion, we argue
why we think this non-competing model is unrealistic; nevertheless, the use of this model
allows us to clearly demonstrate the importance of inter-strain competition to the expected
effects of community-wide IPT interventions.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
We thank the anonymous reviewers for their helpful comments.
Funding: HLM was supported by the Bristol Centre for Complexity Sciences and EPSRC grant EP/5011214. TC
received support from NIH grant DP2OD006663. The content is solely the responsibility of the authors and does
not necessarily represent the official views of the Office of the Director or the National Institutes of Health. CC
received support from EPSRC grant EP/I03626/1.
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Figure 1. Flow chart of the TB model

(a) The core TB model states are repeated three times which allows us to simultaneously
identify classes of individuals by simple HIV-related characteristics: HIV seronegative and
not at risk of HIV (no i), HIV seronegative and at risk of HIV (i = FAR) and HIV
seropositive (i = HIV). Mortality is not shown. Dashed arrows indicate the direct-effect of
IPT. Note that these arrows and the IPT-related states in (b) are only present for the i = HIV
copy of the model since we assume IPT is targeted only to the HIV infected individuals. (b)
Flow chart describing how IPT is implemented in the model: while receiving IPT,
individuals move into separate IPT classes where they can be reinfected with DRTB but are
not susceptible to new DSTB infections. After the IPT course is completed, individuals
retain partial immunity to reinfection (if they were previously infected by M. tuberculosis)
or return to the fully susceptible state (if they were not previously infected).
Figure 2. Results from the model

The prevalence of latent infection (a) and the incidence of active (c) DSTB is lower in the
scenarios with community-wide IPT. In contrast, the prevalence of latent (b) and incidence
of active (d) DRTB is higher in the scenarios with IPT. For this simulation, parameter values
are set to their baseline values as shown in the parameter table in the Supplement.
Figure 3. The trade-off between drug sensitive and drug resistant TB

Increasing rate of receiving IPT and duration of IPT (high values of (tHIV) and (1/w))
produce greater control of active DSTB, but at the expense of a higher incidence of DRTB.
The colour scale indicates the percentage decrease (negative) or percentage increase
(positive) in the different strains.
Figure 4. Varying the competition between strains

(a&c) varying the partial immunity k and kHIV. (b&d) varying the proportion of re-infected
individuals who maintain their original strain dominant in the mixed latent class (d and
dHIV). Parameter values associated with increased competition (i.e. high values of each of
these parameters are consistent with increased inter-strain competition.)
Figure 5. The effect of including acquisition of active DRTB from treatment of active DSTB
Prevalence of latent DRTB infection (A) and incidence of active DRTB infection (B). RAT
stands for Risk of Acquisition from Treatment and is a perentage of the total rate of leaving
the active DSTB class.
Figure 6. Results from the completely non-competing model

(a&c) The prevalence and incidence of DSTB is lower in the scenario with IPT. In contrast
to our model with competition, the prevalence and incidence of DRTB does not significantly
rise in the scenario with IPT (b&d).

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Sci Transl Med. 2013 April 10; 5(180): 180ra49. doi:10.1126/scitranslmed.3005260.

Community-wide isoniazid preventive therapy drives drug-

2Center for Communicable Disease Dynamics, Department of Epidemiology, Harvard School of

after IPT, in models with and without the IPT intervention.

as the selective pressure of community-wide IPT takes effect.

studies) of IPT would be capable of detecting a statistically significant effect.

Materials and Methods

bacilli resulting in a resistant latent infection.

References and Notes

1971; 52:73. [PubMed: 5560737]

Figure 1. Flow chart of the TB model

Figure 2. Results from the model

Figure 3. The trade-off between drug sensitive and drug resistant TB

Figure 4. Varying the competition between strains

Figure 6. Results from the completely non-competing model

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