Journal of Computational and Applied Mathematics 307 (2016) 143–161

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Journal of Computational and Applied

Mathematics
journal homepage: www.elsevier.com/locate/cam

HIV–TB co-infection treatment: Modeling and optimal

control theory perspectives
a b a,∗
Abhishek Mallela , Suzanne Lenhart , Naveen K. Vaidya
a Department of Mathematics and Statistics, University of Missouri-Kansas City, MO, USA
bDepartment of Mathematics, University of Tennessee, Knoxville, TN, USA

article info abstract

Article history: An important question, of whether the initiation of HIV treatment during ongoing TB
Received 30 July 2015 treatment for HIV–TB co-infected individuals is appropriate, still remains unanswered;
Received in revised form 24 February 2016 initiating HIV treatment at or soon after the start of the TB treatment course has some
advantages including fewer HIV-related deaths and a lower risk of HIV transmission as well
Keywords: as some disadvantages including occurrence of Immune Reconstitution Inflammatory
HIV
Syndrome (IRIS) due to a high pill burden. In this study, we develop a mathematical model
TB
to explore the effects of early and late HIV treatment, during the TB treatment course, on
Co-infection dynamics
Mathematical modeling
new HIV infections, HIV-related deaths, and IRIS cases. Mathematical analyses of our
Treatment programs model indicate that co-infection treatment programs alone cannot eradicate the diseases;
Optimal controls additional interventions and/or treatments targeting individuals infected with a single disease
are necessary for successful disease eradication. Numerical computations of the model
solution demonstrate that outcomes of the treatment programs aiming to reduce the total
burden of this co-infection depend highly on both the strength and initiation timing of
antiretroviral therapy (ART). Based on our model, we also formulate an optimal control
problem and solve it using Pontryagin’s Maximum Principle and an efficient numerical
iterative method. Our numerical results of an optimal HIV–TB treatment protocol that yields
a minimum burden from this co-infection indicates that each of the new HIV infections, HIV-
related deaths and IRIS cases is important for achieving optimal benefits from the co-
infection treatment programs.
© 2016 Elsevier B.V. All rights reserved.

1. Introduction

Human immunodeficiency virus (HIV) and Mycobacterium tuberculosis bacteria (Mtb), the causative agent of tuberculosis, are
two infectious agents that have together plagued humans for decades. Importantly, there is ample evidence that the existence of
one of these diseases aggravates the other disease [1–4]. There are several connections between the HIV and tuberculosis (TB)
epidemics. An individual’s acquisition of HIV infection leads to a compromised immune system, consequently increasing
susceptibility to Mtb infections. Tuberculosis is harder to be diagnosed in HIV-infected individuals and is more likely to be fatal if
undiagnosed, left untreated, or not treated in a timely manner [5]. Individuals living with HIV are 30 times more likely to develop TB
than those without HIV [6]. The statistics associated with these two diseases are staggering. As of 2008, around one-third of the
world population was living with TB, 30 million people were infected with

∗
Corresponding author.
E-mail address: vaidyan@umkc.edu (N.K. Vaidya).
http://dx.doi.org/10.1016/j.cam.2016.02.051
0377-0427/© 2016 Elsevier B.V. All rights reserved.
144 A. Mallela et al. / Journal of Computational and Applied Mathematics 307 (2016) 143–161

HIV, and 15 million people were co-infected with HIV and TB [7]. A recent study [8] estimates that India has the highest TB
burden in the world, and accounts for 23% of the global number of approximately 8.8 million TB cases. Of India’s 2 million
TB cases, 5% occurred in HIV-infected individuals. Thus the study of the HIV–TB co-infection is becoming increasingly
important.
HIV is a retrovirus transmitted primarily by needle sharing, unprotected sexual contact, and from mother to child. There is
currently no cure for HIV, but the virulence of HIV in patients can be significantly curbed through the use of antiretrovirals.
Once a person begins antiretroviral therapy (ART), the individual should continue it for life. The primary mode of TB
transmission is inhalation of the germs that are spread by individuals with TB. TB can be cured with a six to nine-month-long
antibiotic treatment.
Due to the different natures and the different treatment outcomes of HIV and TB infections, there is an urgent need of
integrative treatment regimens for HIV–TB co-infected individuals [2,9–11]. Since TB can be effectively cured with treatment
and the complete TB treatment course is short [12,13], the usual recommendation is to begin TB treatment immediately.
Those co-infected individuals undergoing the TB treatment course, however, often face the dilemma of initiating ART [14–
16]. Initiating ART at or soon after the start of the TB treatment course may cause Immune Reconstitution Inflammatory
Syndrome (IRIS) due to a high pill burden of antiretrovirals and antibiotics. Occurrence of IRIS may result in the worsening
of TB infection, causing extremely severe complications with potential discontinuation of treatments [17–21]. Again, delaying
ART until after completion of the TB treatment course poses increased risks of HIV transmission and increased risks of
death due to HIV. Thus, it is critical to identify the ideal combination treatment protocol for co-infected individuals.

Mathematical models are useful to investigate the co-infection population dynamics, and to assess the treatment
programs. Existing models on HIV–TB co-infection [4,22–24] have provided greater insights into the transmission dynamics,
the prevention of new infections, the effects of treatment on the basic reproduction number, and TB drug-resistance issues.
However, none of these models have explored potential programs focused on HIV–TB co-infected individuals. In this study
we develop a novel mathematical model that evaluates treatment strategies for HIV–TB co-infected individuals. In particular,
we focus on the strength and initiation timing of ART for co-infected individuals undergoing TB treatment. Using our model,
we also formulate an optimal control problem to identify the optimal combination treatment protocols that provide minimum
cumulative burden from the HIV–TB co-infection.
The paper is organized as follows: in Section 2, we develop a model that incorporates HIV and TB treatments. In Section
3, we conduct mathematical analyses, including the formulation of the basic reproduction number and the stability analyses
of equilibria. In Section 4, numerical computations of the model solution are performed to explore the effects of HIV–TB
treatment. In Section 5, we formulate an optimal control problem, provide a method of numerical computation, and discuss
optimal control results. We summarize our findings with conclusion in Section 6.

2. Model description

In our model, we include two diseases: HIV and TB. Since the main objective of our model is to assess treatment
programs for co-infected individuals, we do not include single disease treatments. Moreover, since the co-infected
individuals are considered in the critical stage regardless of their stage of individual disease [5,25], we do not consider
different stages of HIV disease and do not distinguish between active TB and latent TB. The WHO recommends TB
screening at the time that HIV infection is diagnosed, before the initiation of antiretroviral therapy and at regular intervals
during follow up [26], and immediate initiation of TB treatment is recommended for co-infected individuals [27]; thus our
model assumes that co-infected individuals begin TB treatment before the initiation of HIV treatment. The TB treatment
course usually completes in six to nine months [6], which our model considers in two phases: an early phase and a late
phase. Based on these assumptions, we consider the following eight mutually exclusive and collectively exhaustive
compartments of the population: susceptible to both diseases (S), HIV-susceptible and TB-infected (T ), HIV-infected and
TB-susceptible (H), co-infected with HIV and TB (C), HIV-infected and undergoing the early phase of TB-treatment (C1),
HIV-infected and undergoing the late phase of TB-treatment (C2), undergoing HIV treatment and the early phase of TB-
M M
treatment (C1 ), and undergoing HIV treatment and the late phase of TB-treatment (C2 ). In the notation above, the
subscripted numbers represent the phases of TB treatment and the superscript M represents treatment for both diseases.
A schematic diagram of the model is given in Fig. 1. Among the top four compartments of Fig. 1, the horizontal arrows
signify individuals without HIV getting infected with HIV due to successful contact with untreated HIV-positive individuals,
namely those in the H, C, C1, or C2 compartments. We assume that treated individuals do not transmit HIV as HIV-treated
individuals have significantly decreased, usually undetected, viral loads. We assume that HIV can be transmitted only
through sexual contact with the sufficient contact rate, β, being a function of the average number of sexual partners, n, the
average condom usage rate, c, and infectivity (the probability per unprotected sexual partnership that an infected individual
transmits the disease to a susceptible individual), θ, according to the formula: β = n(1−c)θ [4]. Similarly, the vertical arrows
in Fig. 1 indicate individuals without TB getting infected with TB due to successful contact with untreated TB patients,
namely those in the T or C compartments. Again, we assume that treated individuals do not transmit TB as TB-treated
individuals are likely under care and closely monitored, thereby reducing infection to others. The TB sufficient contact rate is
denoted by τ.
 A. Mallela et al. / Journal of Computational and Applied Mathematics 307 (2016) 143–161 145

Fig. 1. Schematic diagram of the model. The box compartments represent groups of individuals and the arrows represent recruitment, disease transmission,
treatment, treatment phase transitions, rate of occurrence of IRIS, or death. S = susceptible to both diseases, T = infected with TB, H = infected with HIV, C =
infected with TB and HIV, C1 = infected with HIV and undergoing 1st phase of TB treatment, C2 = infected with HIV and undergoing 2nd phase of TB treatment,
M M
C1 = undergoing HIV treatment and 1st phase of TB treatment, C2 = undergoing HIV treatment and 2nd phase of TB treatment.

Untreated co-infected individuals (in the C compartment) enter the C1 compartment with the TB treatment rate of λ. The
transition rates of the TB treatment phase from the early phase to the late phase and from the late phase to the completion
phase are denoted by ρ1 and ρ2, respectively. The parameters η1 and η2 denote the rates at which individuals begin HIV
treatment during the early phase of TB treatment and the late phase of TB treatment, respectively. We denote the natural
death rate by µ, and disease death rates related to HIV and TB by µH and µT , respectively. The recruitment rate of
susceptibles is denoted by a constant, Λ.
As discussed above, co-infected individuals frequently suffer from IRIS when they are medicated simultaneously for both
M
diseases. We assume that the individuals beginning ART during the early phase of TB treatment, i.e., individuals in the C1
compartment, develop IRIS at the rate γ . It is also known that the earlier the initiation of ART, the higher the probability of
developing IRIS [17–21]. This implies that the rate of IRIS development for individuals initiating HIV treatment during the
M
late phase of TB treatment (i.e., individuals in C2 compartment) decreases as 1/ρ1 increases. Assuming that this rate
decreases linearly from the maximum value, γ , for individuals initiating ART immediately, to the minimum value, 0, for
individuals who do not begin HIV treatment during the TB treatment course, we obtain the rate of IRIS occurrence for
M
individuals in the C2 compartment as γ ρ1/(ρ1 + ρ2). From the medical point of view, this term represents the per capita
rate of IRIS cases generated due to addition of HIV treatment for co-infected individuals who are in the late phase of TB
treatment. With all these assumptions combined, we write the model mathematically as:
d S S
S
,
N − τ ( T + C) N
(2.1)
dt = Λ − µS − β (H + C + C1 + C2)
d S T
T
dt = τ (T + C) N − β (H + C + C1 + C2) N − (µ + µT ) T ,
(2.2)
dH S H
dt = β (H + C + C1 + C2) N − τ (T + C) N − (µ + µH ) H, (2.3)
dC T H
dt = β (H + C + C1 + C2) N + τ (T + C)N − (µ + µT + µH + λ)C,
(2.4)

dC1 = λC − (µ + µH + ρ1 + η1)C1, (2.5)

dt
dC2 = ρ1C1 − (µ + µH + ρ2 + η2)C2, (2.6)
dt
1
4
6

M
dC1

dt
M
dC
2

dt
(2.7)

(2.8)
 M M
where the total population is N(t) = S(t) + T (t) + H(t) + C(t) + C1(t) + C2(t) + C1 (t) + C2 (t).
Using our model, we can compute the total number of new HIV infections, TN , HIV-related deaths, TD, and IRIS cases, TI ,
due to the co-infected population undergoing TB treatment, as follows:
TN = t f β dt,
0
N (S + T )(C1 + C2)
0t
TD = f µH (C1 + C2)dt, (2.9)

TI = 0tf γ C1M + ρ1 + ρ2 C2M ρ

dt,
1

where tf denotes the final time of the study period.

New infections, disease deaths, and IRIS cases are some of the major concerns of HIV–TB epidemiology and co-
infection treatment. Therefore, we take a simple approach and define the total burden for the fixed time interval, [0, tf ], due
to the co-infected population undergoing TB treatment, as follows:
Total Burden = A1TN + A2TD + A3TI ,

where A1, A2, A3 are weightage coefficients assigned to the new infection, the disease death, and the IRIS cases,
respectively. Note that from the medical point of view, the total burden can be regarded as a weighted cumulative sum of
new infections, disease deaths, and IRIS cases. We further note that other possible expressions may be considered for the
total burden depending upon the situations and priorities.

3. Model analysis

3.1. Basic properties of the model

It is easy to verify that the variables in the model system (2.1)–(2.8) remain nonnegative for all t ≥ 0 with nonnegative
initial conditions. We now show that the model is mathematically well-posed. For this, we consider the region
D = {(S, T , H, C, C1, C2, C1M , C2M ) ∈ R8+ : N ≤ Λ/µ}.
The rate of change of the total population is given by
dN
= Λ − µS − (µ + µT )T − (µ + µH )H − (µ + µT + µH )C − (µ + µH )C1
dt

− (µ + µH + ρ2)C2 − (µ + γ )C1M − µ + ρ2 + γ ρ1 C2
M
M
= Λ − µN − µT T − µH H − (µT + µH )C − µH C 1 − (µH + ρ2 )C 2
ρ1 + ρ2 − γ C1M − ρ2 + ρ1 + ρ2 C2

γ ρ1

≤ Λ − µ N.
Clearly, if N > Λ/µ, then dN/dt < 0. Since dN/dt is bounded by Λ − µN, a standard comparison theorem [28] can be used to
−µt Λ −µ Λ Λ
show that N(t) ≤ N(0)e + µ (1 − e t ). In particular, N(0) ≤ µ ⇒ N(t) ≤ µ . Also, we can show that every solution
of the system (2.1)–(2.8) with initial conditions in D remains there for t > 0. The ω-limit sets of the system (2.1)–(2.8) are
contained in D. Thus, D is positively invariant and attracting. Hence the model is mathematically well-posed.

3.2. Basic reproduction number

The basic reproduction number, ℜ0, is defined as the effective number of secondary infections caused by a typical
infected individual during his/her entire period of infectiousness, when he/she is introduced into a population consisting of
susceptible individuals only [29,30]. Here, we formulate ℜ0 using the next-generation matrix method [31,32].
Λ
The model has a unique disease-free equilibrium (DFE): E0 = µ , 0, 0, 0, 0, 0, 0, 0 . For the next-generation method, we
compartments only, i.e., T , H, C, C , and C . The nonnegative matrix, F ,

consider equations corresponding to the infectious 2

1
 A. Mallela et al. / Journal of Computational and Applied Mathematics 307 (2016) 143–161 147

corresponding to the new infections in the population, evaluated at the disease-free equilibrium E0, is given by:

τ 0 τ 0 0
F= 0
0 0
β β β β .
0 0 0
 0 0 0 0 0
0 0 0 0 0

The nonsingular matrix, V, corresponding to the transfer of individuals in and out of compartments, is:
+0 T µ + µH 0 0 0
µ µ 0 0 0 0
+ +
V = 0 0 µ+ µH λ µT λ µ µH 0 ρ1 η1 0 .
0 0 0
0 0 1 H 2 2
− + µ µ ρ η
+ +ρ
0

− 1 + + +
−
Then ℜ0, which corresponds to the dominant eigenvalue of the matrix F V , is given by
−1
ℜ0 = ρ(F V )
where = max{ℜ0H , ℜ0T }, (3.1)

ℜ 0H = β , ℜ 0T = τ .
µ + µH µ + µT
H T
Here, the terms ℜ 0 and ℜ 0 provide the single disease basic reproduction numbers for HIV and TB, respectively. In the
H T
context of co-infection, the overall co-epidemic basic reproduction number, ℜ0, i.e. the maximum of ℜ 0 and ℜ 0 ,
represents the number of secondary infections produced by a single individual infected with the dominated disease, when
he/she is introduced into an entirely susceptible population.
Note that none of the parameters corresponding to co-infection treatment (i.e., ρ1, ρ2, η1, η2) are present in the
expression for ℜ0, indicating no impact of treating co-infected populations on ℜ0. This result is consistent with prior co-
infection models [4,23,24], in which ℜ0 is independent of co-infection treatment.
3.3. Stability analysis of disease-free equilibrium

From results in [32], ℜ0 provides the local stability criteria for the DFE:

Proposition 3.3.1. The DFE of (2.1)–(2.8) is locally asymptotically stable if ℜ0 < 1, and is unstable if ℜ0 > 1.
We are also able to prove that ℜ0 < 1 implies global stability of the DFE as shown in the following theorem:
Theorem 3.3.2. The DFE of (2.1)–(2.8) is globally asymptotically stable if ℜ0 < 1.
Proof. See Appendix. In summary, to prove global stability of DFE with the condition ℜ0 < 1, we first established that when
ℜH0 < 1, the solution curve IH (t) = H(t) + C(t) + C1(t) + C2(t) + C1M (t) + C2M (t) is bounded above by a solution that decays
T T M M
exponentially to zero. Similarly, when ℜ 0 < 1, the solution curve I (t) = T (t) + C(t) + C1(t) + C2(t) + C1 (t) + C2 (t)
is bounded above by a solution that decays exponentially to zero. Combined these two results, we obtain that when
H T M M
max{ℜ 0 , ℜ 0 } < 1, (T , H, C, C1, C2, C1 , C2 ) → (0, 0, 0, 0, 0, 0, 0) as t → ∞. Then we apply the limiting argument
H T
to show that S(t) → Λ/µ as t → ∞, thereby proving the global stability of the DFE when max{ℜ 0 , ℜ 0 } = ℜ0 < 1.
3.4. Quasi disease-free equilibrium

A quasi disease-free equilibrium (QDFE) is an equilibrium state in which only one disease is present. Since TB can be
cured but HIV cannot be cured with currently available treatment, the HIV-QDFE (i.e., the QDFE in which TB is eradicated
but HIV persists) is the only realistically possible QDFE. We solve
S
0=Λ−β H − µS,
N
S
0=β H − (µ + µH )H,
N
and obtain the following HIV-QDFE:

Λ Λ
, 0, (ℜH − 1), 0, 0, 0, 0, 0 .

β − µH β − µH 0

Note that the HIV-QDFE exists if ℜH0 > 1. We now establish the local and global stability of the HIV-QDFE in the
following two theorems:
148 A. Mallela et al. / Journal of Computational and Applied Mathematics 307 (2016) 143–161
Table 1

Model parameters.
Description Entity Estimate (per day for rates) Source
Population of Andhra Pradesh, Tamil Nadu, Maharashtra, and Karnataka N 330,224,000 [33,35]
Initial conditions (populations)
HIV-susceptible, TB-susceptible S(0) 191,514,000 Calculated, estimated
HIV-susceptible, TB-infected T (0) 131,500,000 Calculated, estimated
HIV+, TB-susceptible H(0) 2,405,000 Calculated, estimated
Co-infected C(0) 1,805,000 Calculated, estimated
HIV+, TB-treatment (1st phase) C1(0) 1,000,000 Assumption
HIV+, TB-treatment (2nd phase) C2(0) 1,000,000 Assumption
HIV treatment, TB treatment (1st phase) M 500,000 Assumption
C1 (0)
HIV treatment, TB treatment (2nd phase) M 500,000 Assumption
C2 (0)
Parameters
Recruitment rate Λ 531,000 Estimated [34]
Natural death rate −5 [36]
µ 3.91 × 10
HIV-related death rate −4 [4]
µH 6.85 × 10
TB death rate −4 [4]
µT 5.48 × 10
−4
HIV sufficient contact rate β 5.12 × 10 Estimated
TB sufficient contact rate −2 [4]
τ 1.10 × 10
HIV early treatment rate η1 0 to 0.05 Varied
HIV late treatment rate η2 0 to 0.05 Varied
−1
TB treatment rate λ 1 × 10 Estimated
ρ −3
TB treatment phase transition rate (Phase 1 to Phase 2) 1 5.56 × 10 Calculated, varied
−2
TB treatment phase transition rate (Phase 2 to completion) ρ2 1.11 × 10 Calculated, varied
Rate of occurrence of IRIS γ −3 Estimated [17]
1 × 10

H
Theorem 3.4.1. The HIV-QDFE is locally asymptotically stable if ℜ 0 > 1, ℜT0 < 1.

Proof. See Appendix. In summary, we calculated the Jacobian of the model evaluated at the HIV-QDFE. Then we showed
H
that the real parts of the eigenvalues are negative if ℜ 0 > 1 and ℜT0 < 1.
H
Theorem 3.4.2. The HIV-QDFE is globally asymptotically stable if ℜ 0 > 1, ℜT0 < 1.
M M
Proof. See Appendix. In summary, as in Theorem 3.3.2, we first showed (T , C, C1, C2, C1 , C2 ) → (0, 0, 0, 0, 0, 0) as
t → ∞. Then using the limiting arguments, we considered the S − H plane as the long-term behavior of the system would be
identical to its behavior on the S − H plane. We then applied the Poincaré–Bendixson theorem and ruled out a periodic orbit with
the Bendixson–Dulac criterion. After determining that the DFE is an unstable saddle with stable manifold along the S-axis, we finally
H T
concluded that the HIV-QDFE is globally asymptotically stable if ℜ 0 > 1, ℜ 0 < 1.

4. HIV–TB co-infection treatment: model predictions

4.1. Parameter estimation

We estimated the model parameters based on the literature survey [4,17,33–36]. A prior study of the HIV–TB co-
epidemic [4] considered the population in India, given the high prevalence of these infectious diseases in India. To be
consistent with this study, we chose the population in four Indian states, namely Maharashtra, Andhra Pradesh, Karnataka,
and Tamil Nadu. The population of the four Indian states in our study was 330,224,000 [ 33,35]. We obtained the initial pop-
ulation sizes of the S, T , H, and C compartments from Long et al. [4]. Assuming that the population was uniformly
distributed across age groups, we calculated the recruitment rate Λ to be 531,000 [34].
The natural death rate was estimated based on the average life expectancy of people in India [ 36]. We used the values
estimated in Long et al. [4] for the HIV death rate, the HIV contact rate, the TB death rate, and the TB infection rates. The
rate of occurrence of IRIS was estimated using study data from [17]. Since some parameters are not available in the
literature, we set reasonable values for them, and varied them during our simulation. The parameters used for our
simulations are given in Table 1.
For our model predictions, we focus on the total new HIV infections, TN , HIV-related deaths, TD, and IRIS cases, TI , due
to the co-infected population undergoing TB treatment. For the sake of demonstration, we compute the totals over a period
of one year, i.e., tf = 365 days. Since we do not know values for the weightage coefficients, for simplicity, we take A1 = A2 =
A3 = 1 for our model simulations. However, we consider various weightage factors in the optimal control solutions.
 A. Mallela et al. / Journal of Computational and Applied Mathematics 307 (2016) 143–161 149

Fig. 2. Effect of the strength of early and late HIV treatment programs. (a) The total new HIV infections, (b) the total HIV-related deaths, (c) the total IRIS cases,
and (d) the total burden, as, η1 (early HIV treatment rate) and η2 (late HIV treatment rate) are varied between 0 and 0.05. Diagonals represent η1 = η2 and anti-
diagonals represent η2 = 0.05 − η1. Quantities on the color bars are in millions. (For interpretation of the references to color in this figure legend, the reader is
referred to the web version of this article.)

4.2. Effect of strength of antiretroviral therapy program

In our model, we represent the strength of the co-infection treatment program using the parameters η1 (early HIV treat-
ment rate) and η2 (late HIV treatment rate). We observe how changes of these parameters affect TN , TD, TI (Fig. 2(a), (b),
(c)) and the total burden (Fig. 2(d)). While we considered the entire region η1, η2 ∈ [0, 1] in our computations, for the pur-
pose of demonstration, only the region η1, η2 ∈ [0, 0.05] is considered (Fig. 2(d)) as the magnitudes of TN , TD, TI are
mostly sensitive in this region. From our simulations with the entire region [0, 1] (data not shown), we identified only
negligible change of TN , TD, TI for η1, η2 greater than 0.05. Therefore, we fixed an upper bound of 0.05 for both η1 and η2.
Note that our qualitative conclusions remain the same when the entire region is considered.
In a treatment program with only early treatment (i.e., η2 = 0), an increase in η1 from 0 to 0.05 decreases TN and TD from 527
thousand to 107 thousand and from 713 thousand to 145 thousand, respectively, and increases TI from 93 thousand to 715
thousand. In this case, the total burden decreases from 1333 thousand to 967 thousand. Similarly, with η1 = 0 (late treatment only),
if η2 is increased from 0 to 0.05, TN decreases from 527 thousand to 382 thousand, TD decreases from 713 thousand to 517
thousand, and TI increases from 93 thousand to 186 thousand. In this case, the total burden decreases from 1333 thousand to
1085 thousand. Note that the changes in the three quantities are more sensitive to early treatment than to late treatment. However,
the total burden is slightly lower for (η1, η2) = (0.05, 0) than for (η1, η2) = (0, 0.05) (Table 2).
In a treatment program that places equal emphasis on the early and the late HIV treatments, i.e., when η1 = η2 (along
the main diagonal in Fig. 2(a), (b), (c)), the effects are magnified; with η1 = η2 = 0.05, TN decreases to 57 thousand, TD
decreases to 77 thousand, and TI increases to 744 thousand. Also, the total burden decreases to 878 thousand (Fig. 2(d)).
150 A. Mallela et al. / Journal of Computational and Applied Mathematics 307 (2016) 143–161

Table 2
New HIV infections, HIV-related deaths, IRIS cases, and the total burden (in thousands) for various strengths of early and late
treatment programs.
HIV infections HIV-related deaths IRIS cases Total burden

(η1 , η2) = (0, 0) 527 713 93 1333

(η1 , η2) = (0, 0.05) 382 517 186 1085
(η1 , η2) = (0.05, 0) 107 145 715 967
(η1 , η2) = (0.05, 0.05) 57 77 744 878

Fig. 3. Effect of initiation timing of HIV treatment. The total burden, with 1/ρ1 varied between 1 and 269 days, η2 varied between 0 and 0.05, η1 = 0, and 1/ρ2 =
270 − 1/ρ1. Quantities on the color bar are in millions. (For interpretation of the references to color in this figure legend, the reader is referred to the web version
of this article.)

The endpoint values of each of the η1 × η2 color plots are presented in Table 2. Finally, note that the case η1 + η2 = 0.05
(along the anti-diagonal in Fig. 2(a), (b), (c)) can be considered to represent constrained resource allocation. Importantly, in
such resource-limited settings, the minimum value of the total burden occurs at some interior value of η1 and η2 = 0.05−η1
(along the anti-diagonal in Fig. 2(d)), instead of at the boundary values. In this particular simulation, the minimum occurs at
η1 = 0.031 and η2 = 0.019. The values η1 = 0.031 and η2 = 0.019 in this case imply that a weight distribution allocating
62% of available resources for early HIV treatment and the remaining 38% of resources for late HIV treatment would yield a
minimum total burden. With this weight distribution, the minimum total burden is obtained as 920 thousand with
corresponding TN , TD, and TI values of 96 thousand, 130 thousand, and 694 thousand, respectively.

4.3. Effect of initiation timing of antiretroviral therapy

For the base case computation, we assumed the average time spent during early TB treatment is 180 days and the average
time spent during the late TB treatment is 90 days. In our model, 1/ρ1 represents the average time spent by co-infected
1
people in the early phase of the TB treatment course while = 270 − 1 , with 270 days being the duration of the TB
ρ2 ρ1
treatment course, represents the average time spent in the late phase of the TB treatment course. If we set η 1 = 0 (no HIV
treatment during the early TB treatment phase) and η 2 ≥ 0 (HIV treatment with rate η 2 during the late TB treatment phase), the term
1/ρ1 in this case represents the average time the co-infected individuals under TB treatment wait before they begin
1 1
HIV treatment at rate η2. Therefore, by taking η1 = 0, η2 ≥ 0, and varying 1/ρ1 with = 270 − ρ2 , we can evaluate
ρ1
the effects of the initiation timing of ART on the treatment outcomes. For this purpose, we thus set η 1
= 0, and vary 1/ρ 1
1 1

between 1 and 269 days, with ρ1 = 270 − ρ2 . To observe the effect of initiation timing for various treatment rates, we also
vary η2 between 0 and 0.05.
As shown in Fig. 3, in addition to the strength of the treatment program, the initiation timing has significant impact on the
total burden; in some cases, a total burden of more than 300 thousand can be reduced by proper choice of initiation timing.
More importantly, for fixed values of treatment strength, the total burden is minimized at some interior values of 1 /ρ1. For
example, for the treatment rate of η2 = 0.05, the minimum total burden is obtained at 1 /ρ1 = 182 days, with the value of the
minimum total burden equal to 1087 thousand. These results clearly show that the initiation timing is critical for achieving
the optimal outcome from this treatment program.
Our numerical results suggest that there is a significant impact of both the strength of treatment program and
the initiation timing of ART on the outcome of a co-infection treatment program, thereby demanding an optimal
treatment protocol, which we discuss in the sections to follow.
 A. Mallela et al. / Journal of Computational and Applied Mathematics 307 (2016) 143–161 151

5. Optimal control

Our goal here is to find an optimal treatment strategy for co-infected individuals that will minimize the total burden, while
minimizing the cost of implementing such a strategy.

5.1. Formulation

We introduce time-dependent controls, η1 = u1(t), the early treatment rate, and η2 = u2(t), the late treatment rate, into
the model. This results in the following system:
dS S S
, (5.1)
dt = Λ − µS − β (H + C + C1 + C2) N − τ ( T + C) N
dT S T
(5.2)
dt = τ (T + C) N − β (H + C + C1 + C2)N − (µ + µT ) T ,
dH S H
− τ (T + C)N − (µ + µH ) H, (5.3)
dt = β (H + C + C1 + C2) N
dC T H
(5.4)
dt = β (H + C + C1 + C2) N + τ (T + C)N − (µ + µT + µH + λ)C,
dC1 = λC − (µ + µH + ρ1 + u1)C1,
(5.5)
dt
dC2 = ρ1C1 − (µ + µH + ρ2 + u2)C2,
(5.6)
dt
M M
dC1
(5.7)
dt = u1C1 − (µ + ρ1 + γ )C1 ,
M M M
dC2 γ ρ1
+ρ + ρ (5.8)
dt = u2C2 + ρ1C1 − µ + ρ2 1 2 C2 ,
where
M M
N(t) = S(t) + T (t) + H(t) + C(t) + C1(t) + C2(t) + C1 (t) + C2 (t).

Note that for nonnegative initial conditions and bounded Lebesgue measurable controls, the state system admits
nonnegative bounded solutions [37]. The objective functional that we seek to minimize over a finite time horizon [0, tf ] is:
tf
0 (5.9)
J(u1, u2) = A1TN + A2TD + A3TI + A4 (u12 + u22) dt
t
f β
= 0 A1 N (S + T )(C1 + C2) + A2µH (C1 + C2) (5.10)
C M+
+ A3γ 1 ρ1 + ρ2 C2M + A4(u12 + u22) dt.

ρ1

Here, A1, A2, and A3 represent the balancing factors associated to the total numbers of new HIV infections, TN , HIV-related
deaths, TD, and IRIS cases, TI , respectively, due to the co-infected population undergoing TB treatment. The balancing
2 2
factor associated to the cost component, u 1 + u 2, is denoted by A4.
We consider the set of admissible (bounded) control functions given by
∞
Γ = (u1, u2) ∈ L (0, tf )2|(u1(t), u2(t)) ∈ [0, ub1] × [0, ub2] ∀t ∈ [0, tf ] ,

b b
where tf denotes the final time of the study period and u1, u2 are Lebesgue measurable with upper bounds u 1, u 2,
∗ ∗
respectively. Thus, we seek an optimal control pair (u 1, u 2) such that
∗ ∗
J(u 1, u 2) = min J(u1, u2).
Γ

5.2. Optimality system

The existence of the optimal control follows from standard results due to the structure of the state system and the
∞
uniform L bounds on the states and the controls [38].
To characterize the optimal controls we use Pontryagin’s Maximum Principle [39], which allows us to utilize adjoint
functions to transform the optimization problem into a problem of determining the pointwise minimum of the Hamiltonian,
152 A. Mallela et al. / Journal of Computational and Applied Mathematics 307 (2016) 143–161

relative to u1 and u2. The Hamiltonian is constructed from the functional (5.9), with the underlying state dynamics
attached:
H = A1 N (S + T )(C1 + C2) + A2 [µH (C1 + C2)] + A3γ C1M + ρ1 ρ2 C2
M
+ A4 u12 + u22
β ρ1
S S +

+ λ1 Λ − µS − β (H + C + C1 + C2) N − τ ( T + C) N
+ λ2 τ (T + C) N − β (H + C + C1 + C2) N − (µ + µT ) T
S T
S
H
+ λ3 β (H + C + C1 + C2) N − τ (T + C) N − (µ + µH ) H
T H
+ λ4 β (H + C + C1 + C2) N + τ (T + C) N − (µ + µT + µH + λ)C
+ λ5 [λC − (µ + µH + ρ1 + u1)C1] + λ6 [ρ1C1 − (µ + µH + ρ2 + u2)C2]
M M +
+ λ7 u1C1 − (µ + ρ1 + γ )C1 + λ8 u2C2 + ρ1C1 − µ + ρ2 ρ1 + ρ2 C2M (5.11)

γ ρ1

where λi, i = 1, . . . , 8, are the adjoint variables associated to the states

M M
S, T , H, C, C1, C2, C1 , C2 .
For our system of ODEs, we are able to use Pontryagin’s Maximum Principle to obtain adjoint functions, which track the
changes in our objective functional due to the state variables. The theorem below gives the ODE system and the boundary
conditions for our adjoint functions and the corresponding characterization of an optimal control pair. The optimality system
consists of our state and adjoint systems together with this control characterization, and we will solve this optimality system
numerically to obtain the optimal controls. The optimality system of equations results from taking the appropriate partial
derivatives of (5.11) with respect to the associated state variable.
∗ ∗ ∗ ∗ ∗ ∗ ∗
Theorem 5.2.1. There exists an optimal control pair (u 1, u 2) and corresponding solution vector, (S , T , H , C , C1 ,
∗ M∗
C2 , C1 , C2M∗ ), that minimizes J(u1, u2) over Γ . Furthermore, there exist adjoint functions λ1(t), λ2(t), . . . , λ8(t) (see
Appendix for the expression of dλi/dt) with transversality conditions
λi(tf ) = 0, i = 1, . . . , 8.

Here,
E ∗ ∗ ∗ ∗
= H + C + C1 + C2
and
∗ ∗ ∗ ∗ ∗ ∗
N=S +T + H + C + C1 + C2 + C1M∗ + C2M∗ .
Also, the following characterization holds:
u1 = min u1 max 0 ∗
C (λ λ) (5.12)
t 1 2A4

∗( ) b, ,
u2 = min u2 max 0 C∗(λ λ)
2
t
2A4

) , .
∗( b ,
Proof. Corollary 4.1 of [38] gives the existence of an optimal control pair due to the convexity of the integrand of (5.10) with
respect to (u1, u2), a priori boundedness of the state solutions, and the Lipschitz property of the state system with respect to
the state variables. Applying Pontryagin’s Maximum Principle, we obtain the adjoint system
dλ1 ∂H dλ2 ∂H dλ8 ∂H
, ,..., ,
dt = − ∂S dt = − ∂T dt = − ∂C2M
with zero final time conditions. To get the characterizations of the optimal control given by (5.12), we solve the equations on
the interior of the control set,
∂H ∂H
= 0, = 0.
∂ u1 ∂ u2
Using the bounds on the controls, we obtain the desired characterization.
 A. Mallela et al. / Journal of Computational and Applied Mathematics 307 (2016) 143–161 153

The optimality system consists of the state system with the initial time conditions, the costate (adjoint) system with the
terminal time conditions, and the control characterizations. Due to a priori boundedness of the state and adjoint systems, we
obtain the uniqueness of the optimal control for small final time tf . This small time condition is due to opposite time
orientations of the state system and the adjoint system [40].
We note that the controls u1 and u2 are chosen independently but their optimal choices are related due to coupling in the
system.

5.3. Method of numerical computations: optimality system

We implement an iterative procedure to numerically solve the boundary value problem of the optimality system,
consisting of 16 ordinary differential equations comprising the state and adjoint equations, coupled with the two control
characterizations. Numerical computation begins with an initial guess for the controls and then uses a forward fourth-order
Runge–Kutta scheme to solve the state equations over the time interval [0, tf ] partitioned into N subintervals. Using the
resulting state values and the given final time values, the adjoint system is then solved backward in time (due to the
transversality conditions), again using a fourth-order Runge–Kutta method. Then, the controls are updated by using a
convex combination of the previous controls and the values from the characterizations. This iterative process continues until
convergence, which is set to occur when the relative error between all state variables, the adjoint functions, and the
∥x(k)∥

∥x(k)−x(k−1)∥
control functions is less than a specified value δ, i.e., when ≤ δ, where ∥ · ∥ is the L∞-norm. The method of numerical computation discussed above can be summarized as the algorithm below [40]:

Here, ⃗x = (x1, . . . , x8) and κ⃗ = (κ1, . . . , κ8) denote the vector approximations for the states and adjoints.

Step 1: Make initial guesses for u1, u2 over the interval [0, tf ].
(k) (k ) (k−1)
Step 2: While (δ∥x ∥ − ∥x − x ∥ < 0) do Steps 3–5.
Step 3: Solve ⃗x forward in time (using a 4th-order Runge–Kutta scheme) according to its system of differential
equations in the optimality system.
Step 4: Using the transversality condition κ8 = κ(tf ) = 0 and the stored values for u1, u2, ⃗x, solve κ⃗ backward in
time (using a 4th-order Runge–Kutta scheme) according to its system of differential equations in the
optimality system.
Step 5: Update u1, u2 by entering the new ⃗x and κ⃗ values into the characterization of the optimal controls.
To ascertain that the iteration convergence is met and to obtain meaningful optimal control profiles, reasonable estimation of
balancing factors A1, A2, A3, A4 is critical. To estimate these balancing factors, we first compute the median values of TN (≈106
thousand), TD (≈144 thousand), and TI (≈672 thousand) from the region (η1, η2) ∈ [0, 0.05] × [0, 0.05] (Fig. 2(a), (b), (c)). Each
η1 and η2 was discretized into 51 values, yielding approximately 2600 values in total. The median values of η1 and η2 are both
0.025. The treatment has a tendency to change TN and TD in one direction and TI in another direction; for example, an increase in
the early treatment rate decreases TN and TD, and increases TI . Therefore in the balanced
situation, we have
A1TN + A2TD = A3TI . (5.13)

Then, giving equal importance to the total new infections and the total deaths, i.e.,
A1TN = A2TD, (5.14)

we obtain A1/A3 = 3.17 and A2/A3 = 2.33. Also, balancing the total cost, we obtain
A1TN = A4 0 tf 365 2
2 + 2 2 (5.15)
0.05 0.05
( u12 + u22) dt ≈ A4 0 dt ≈ 0.46A4.

This implies A4/A3 = 730 500. Hence, for the base-case computations, we take A1 = 3.17, A2 = 2.33, A3 = 1, and

A4 = 730 500.

5.4. Numerical results: optimal control

We first examined numerically the convergence of our computational method. We performed all numerical computations
in MATLAB R2013b on a 1.9 GHz Dell computer running Windows 7. We set the value of δ to be 0.001 for all our
computations. For the base-case, i.e. (A1, A2, A3, A4) = (3.17, 2.33, 1, 730 500), it took 12 iterations and 5 s of CPU time to
meet the convergence criteria. The convergence of this method could also be easily obtained when A1, A2, A3 are varied
−4 4 −6 6
from 10 to 10 and A4 is varied from 10 to 10 . In these ranges, the maximum number of iterations for all runs was 16
and the maximum CPU time was 7 s. This shows that the numerical method used is efficient in achieving convergence for a
wide range of balancing factors.
∗ ∗
For the base-case (A1, A2, A3, A4) = (3.17, 2.33, 1, 730 500), we obtained the profile of optimal controls u 1 and u 2
as shown in Fig. 4(a). Throughout the entire treatment program period, the early treatment rate needs to be higher than the
154 A. Mallela et al. / Journal of Computational and Applied Mathematics 307 (2016) 143–161

and (c) A4 =

Table 3
Outcome of optimal control solutions: HIV-related deaths, TD , new HIV infections, TN , IRIS cases, TI , and the total burden (in
thousands).
A4 TD TN TI Total burden

Without controls 713 527 93 1333

Including all of TN , TD , TI (A1 = 3.17, A2 = 2.33, A3 = 1)

730,500 (base-case) 126 93 696 915
146,100 89 66 733 888
29,220 79 58 743 880

IncludingTN , TDonly(A1 = 3.17, A2 = 2.33, A3 = 0)

730,500 118 87 705 910
146,100 86 63 736 885
29,220 78 58 743 879

IncludingTI only(A1 = 0, A2 = 0, A3 = 1)
730,500 713 527 93 1333
146,100 713 527 93 1333
29,220 713 527 93 1333
 ∗ ∗
Fig. 4. Effect of including IRIS in the optimal control. Optimal control solutions u 1, u 2 for A1 = 3.17, A2 = 2.33 with (a) A4 = 730 500, (b) A4 = 146 100,
29 220.

late treatment rate to achieve optimal benefits from these controls. With these controls, 587 thousand deaths and 434
thousand new infections are avoided compared to the scenario of no controls (Table 3). Because of these early treatments,
603 thousand IRIS cases are generated. Overall, the total burden of thousand are reduced using this optimal control
∗ ∗
strategy. We also note that the lower the value of A4, the higher the level of optimal controls u 1 and u 2 (Fig. 4(a), (b), (c))
as expected. As a result, with lower values of A4, comparatively more deaths and more new infections are avoided, and
more IRIS cases are generated (Table 3).
∗ ∗
To study the importance of considering IRIS cases in optimal control solutions, we computed the solutions u 1 and u 2
for A3 = 0 and A3 = 1 with different values of A4 (Fig. 4(a), (b), (c)). We observe that the effect of considering IRIS cases is
∗ ∗
more pronounced for u 1 than for u 2. This is consistent with the fact that IRIS cases are more responsive to the strength
of early HIV treatment than to the strength of late HIV treatment in the presence of TB treatment. With A1, A2, A4 at base-
case values, excluding IRIS cases in the optimal control problem (i.e., changing A3 from 1 to 0) results in higher optimal
controls with 8 thousand fewer deaths, 6 thousand fewer infections, and 9 thousand more IRIS cases ( Table 3). These
effects are amplified on A4 (Table 3).
Similarly, we studied the importance of considering deaths and new infections in the optimal control solutions. When TD
and TN are excluded and only TI is included in the objective functional (i.e., A1 = 0, A2 = 0, A3 = 1), the optimal controls in
∗ ∗
this case are u 1 = 0 and u 2 = 0, i.e. no treatment, regardless of the value of A4 (Fig. 5(a), (b), (c)). This is because in
such scenarios there is no penalty for deaths or new infections, thereby making the absence of treatment favorable to
minimize the total IRIS cases. Therefore, considering deaths and new infections along with IRIS cases is extremely
important in developing proper optimal treatment protocols.

6. Conclusion

Among the numerous infectious agents that have afflicted humans for millennia, the past few decades have shown that
HIV and Mtb interact dangerously in humans. Although the scientific community has come a long way in parrying the threats
of these two infectious agents, much work is left to be done in regard to co-infection treatment.
In this study, we developed a novel mathematical model that incorporates various aspects of treatments for HIV –TB co-
infected individuals. We conducted thorough analyses of the model, including formulation of the basic
reproduction
 A. Mallela et al. / Journal of Computational and Applied Mathematics 307 (2016) 143–161 155

∗ ∗
Fig. 5. Effect of including new HIV infections and HIV-related deaths in the optimal control. Optimal control solutions u 1, u 2 for A3 = 1 with (a) A4 = 730 500,
(b) A4 = 146 100, and (c) A4 = 29 220.

number and stability of the disease-free and the quasi disease-free equilibria (defined as a state where one disease is
eradicated, whereas the other disease remains endemic). Our analyses show that the co-infection treatments play no role in
the basic reproduction number or the stability of the disease-free and HIV quasi-disease free equilibria. This implies that
single disease treatments need to be incorporated with co-infection treatments for disease eradication, which is consistent
with observations in prior co-infection studies [4,23,24].
Our model simulations demonstrate that the total burden from this co-infection can be minimized using carefully chosen
strengths and initiation timing of ART in the treatment programs. Hence, we also formulated an optimal control problem and
identified optimal treatment programs for co-infected individuals. According to our results, each of disease deaths, new
infections, and IRIS cases plays an important role on optimal control solutions, and the early treatment rate needs to be
higher than the late treatment rate throughout the entire treatment program to achieve minimum total burden from this co-
infection.
Our model has some limitations. We have ignored the possibilities of virus mutations, drug-resistant strains of TB and/or
HIV, as well as progressively changing infection rates in order to simplify the model. We assumed that all individuals in a
given compartment are identically infectious, which might ignore potential effects caused due to variation among individuals.
As discussed in previous studies, single-disease models with only HIV or TB may overestimate or underestimate the extent
of infection [4]. Therefore, our results may differ from the results of single-disease models. We also acknowledge that many
of our parameters are based on single-disease studies as there are limited co-infection studies available. Therefore, more
data and more reliable parameters relevant to co-infection dynamics can further improve our results. Finally, more concrete
and realistic quantification of the balancing factors of the objective functional is necessary in order to refine the optimal
treatment regimen and ensure a successful control protocol of HIV and TB.

Acknowledgments

This work was funded by the start-up fund from the University of Missouri-Kansas City (#KCS28) and the UMRB grant
from the University of Missouri Research Board (#KDA91). Research of AM was assisted by attendance as a Short-term
Visitor at the National Institute for Mathematical and Biological Synthesis (NIMBioS), an Institute sponsored by the National
Science Foundation through NSF Award #DBI-1300426. SL also acknowledges the support from NIMBioS through NSF
Award #DBI-1300426, with additional support from The University of Tennessee, Knoxville. The authors would like to thank
three anonymous reviewers for their constructive suggestions that helped improve the paper.

Appendix

Global asymptotic stability of the DFE

H
Proof of Theorem 3.3.2. Let I denotes the total number of HIV-infected individuals, i.e.,
H M M
I = H + C + C1 + C2 + C1 + C2 .

Then,
dI
H S T

dt = β(H + C + C1 + C2) N + β(H + C + C1 + C2) N − (µ + µH )H − (µ + µT + µH )C

− (µ + µH )C1 − (µ + µH + ρ2)C2

≤ β(H + C + C1 + C2) − (µ + µH )H
− (µ + γ )C1M − µ + ρ2 + γ

− (µ + µT + µH )C − (µ +
µH )C1 − (µ + µH + ρ2)C2
156 A. Mallela et al. / Journal of Computational and Applied Mathematics 307 (2016) 143–161
 − (µ + γ )C1M − µ + ρ2 + γ ρ1 C2
M

ρ1 + ρ2
= [β − (µ + µH )] H + [β − (µ + µT + µH )] C + [β − (µ + µH )] C1 + [β − (µ + µH + ρ2)] C2
 − (µ + γ )C1M − µ + ρ2 + γ ρ1 C2
M

ρ1 + ρ 2
≤ εIH ,
H H
where ε = β−(µ+µH ). If ℜ 0 < 1, then ε < 0. This implies that the solution curve I (t) is bounded above by a solution that decays
H
exponentially to zero if ℜ 0 < 1. Following a similar argument, it is easy to show that the solution curve representing the total
T M M
number of TB-infected individuals, denoted by I = T +C +C1 +C2 +C1 +C2 , is bounded above by a solution that
T H T M M
decays exponentially to zero, if ℜ 0 < 1. Therefore, if max {ℜ 0 , ℜ 0 } < 1 and (T , H, C, C1, C2, C1 , C2 ) ̸= (0, 0, 0, 0, 0, 0,
H T H T M M
0), then I (t) and I (t) decrease, and eventually I (t), I (t) → 0 as t → ∞. Since T , H, C, C1, C2, C1 , C2 ≥ 0, each of {T , H,
M
C, C1, C2, C1 , C2M } approaches zero in the limit as t → ∞; i.e., (T , H, C, C1, C2, C1M , C2M ) → (0, 0, 0, 0, 0, 0, 0) as
t → ∞. This implies that
dS
= Λ − X(t)S(t)
dt
β τ
with X(t) = µ + N (H + C + C1 + C2) + N (T + C) → µ as t → ∞. Thus we have:
(∀ν > 0)(∃tT > 0) such that (t > tT ) =⇒ dt − (Λ − µS) < ν.
dS

Thus we can conclude that for all t, ν > 0,

µt
dt e − (Λeµt − µSeµt ) < νeµt
dS
d µt µt µt

(Se ) Λe < νe
−

=⇒ dt
µt d µt µt

=⇒ (Λ − ν)e < dt (Se ) < (Λ+ ν)e µ e

=⇒ µ e +K Se +K 1 2
+ K3
Λ− ν µ t
< µ t
< Λ+ν µt

=⇒ µ + K4e S µ + K5 e
Λ−ν < Λ +ν
−µt < −µt ,
where K1, K2, and K3 are arbitrary constants of integration, with K4 = K1 − K2 and K5 = K3 − K2. In words, S is squeezed to
Λ/µ. So limt→∞ S(t) = Λ/µ. Hence, the disease-free equilibrium is globally asymptotically stable if ℜ0 < 1.
Local asymptotic stability of the HIV-QDFE

Proof of Theorem 3.4.1. We establish the local stability of the HIV-QDFE using the following method. We obtain the
M M
Jacobian, J, of the model, which is a matrix of partial derivatives with respect to the variables S, H, T , C, C , C , C , C :
1 2 1 2

X β 2 X
2
(β − τ − X)X X(τ + X) 2 2 (β − X)X (β − X)X
µH X X X
−
+ − β − −2 −2
ββ β
−
2
β β

βββ
(X − )
ββ)X
(X − (X − β)(X
β +τ) β
X + τ (X − β) β
X X
β
β
(X − β) X
β
(X −
β β)X

0 0 µ µ β τX τX 0 0 0 0
H T
− − + β β

(β X )(β τ) τX
0 0 − β
+ τ −
µT −
λ X − −
β 0 0 0 0
0 0 0 λ X ρ1 η1 0 0 0

− − −
0 0 0 0 ρ 1 − X − ρ 2− η 2 0 0

0 0 0 0 0 −µ − ρ − γ 0
η1 1
γ ρ1
0 0 0 0 0 η 2 ρ 1 µ ρ 2 ρ ρ

− − − 1 + 2

where X = µ + µH . Note that the order of the variables used to compute the Jacobian has been changed.
We then determine its eigenvalues. First, we present the eigenvalues of the Jacobian evaluated at the HIV-QDFE and
then establish the negativity of their real parts. Let ξi, i = 1, 2, . . . , 8 denote the eight eigenvalues.
ξ1 = −(µ + ρ1 + γ )
 A. Mallela et al. / Journal of Computational and Applied Mathematics 307 (2016) 143–161 157

(µ + ρ2)(ρ1 + ρ2) + ρ1γ

ξ2 = −
ρ1 + ρ 2
ξ3 = −(µ + µH + ρ2 + η2)
ξ4 = −(µ + µH + ρ1 + η1)
1 √
ξ5 = − (β − µH + σ)
2
1 √
ξ
ξ6 = −2 (β − µH − σ ) √
Σ
7 = −2β β(µ + 2µT + λ + β − τ) +

1 Σ,
ξ √
8 = −2β β(µ + 2µT + λ + β − τ) −
1

where
1
σ = (β − µH )[4(µ + µH )2 + β(β − 4µ − 5µH )]
β
and
Σ
= β(β3 − 2β2λ − 2β2µ − 4β2µH + 2β2τ + βλ2 + 2βλµ + 4βλµH − 2βλτ + βµ2
+ 4βµµH − 2βµτ + 4βµ2H − 4βµH τ + βτ2 + 4λµτ + 4λµH τ + 4µµH τ + 4µ2H τ ).
Clearly Re(ξ1), Re(ξ2), Re(ξ3), and Re(ξ4) are negative. We proceed to show that Re(ξ5), Re(ξ6) are negative. Observe ℜH0 = β/(µ +
µH ) > 1 ⇒ β − µH > µ. Now we have two cases:
Case 1: σ ≤ 0. 1
√ √
If σ < 0, then σ is a pure imaginary number. So Re( σ ) = 0 and Re(ξ5) = Re(ξ6) = − 2 (β − µH ) < 0. If σ = 0, then
Re(ξ5) = Re(ξ6) < 0.
Case 2: σ > 0.
√
Subcase 2.1: σ is positive.
Note that (β − µH ) + √σ > µ + √ σ > 0 =⇒ Re(ξ5) < 0. Now
ℜH0 > 1 =⇒ 4(µ + µH )(β − µ − µH ) > 0
=⇒ β(β − µH ) − [4(µ + µH )2 + β(β − 4µ − 5µH )] > 0
1
=⇒ (β − µH )2 − β (β − µH )[4(µ + µH )2 + β(β − 4µ − 5µH )] > 0
=⇒ (β − µH )2 − σ > 0
√

=⇒ (β − µH ) − σ > 0
=⇒ Re(ξ6) < 0, (A.1)
√ > 0.
with (A.1) following because β − µH > 0 and σ
√
Subcase 2.2: σ is negative.
Then Re(ξ6) < 0. But
√ √ ⇐⇒ (β − µH )2 > σ
Re(ξ5) < 0 ⇐⇒ (β − µH ) + σ > 0 ⇐⇒ (β − µH ) > − σ
⇐⇒ (β − µH )2 − σ > 0 ⇐⇒ ℜ0H > 1 [same as Subcase 2.1].

We now show that Re(ξ7), Re(ξ8) are negative. Consider the following cases:

Case 1: Σ ≤ 0.√ √
If Σ < 0, then Σ is a pure imaginary number and thus Re( Σ ) = 0. So
1
Re(ξ7) = Re(ξ8) = − (µ + 2µT + λ + β − τ )
2
1
= (τ − µ − µT − λ − β − µT )
2
< 0,
T τ
< 1 =⇒ τ − µ − µT < 0. If Σ = 0, clearly Re(ξ7) = Re(ξ8) = 0.
because ℜ0 = µ+µT
158 A. Mallela et al. / Journal of Computational and Applied Mathematics 307 (2016) 143–161
Case 2: Σ > 0.
√
Subcase 2.1: Σ is positive. Then Re(ξ7) < 0. Observe
Re(ξ8) < 0 ⇐⇒ β(µ + 2µT +λ+β−τ)− √ >0
Σ
√
⇐⇒ β(µ + 2µT +λ+β−τ)>
Σ
2 2 (A.2)
⇐⇒ β (µ + 2µT + λ + β − τ ) − Σ > 0
⇐⇒ −4β(βµH2 2 2 2 2
− β µ − β λ − β µH − βµT − β µT + β τ + 2 2
µH2 τ
+ βλµH − βλµT + βµµH − βµµT − βµH τ + βµT τ + λµτ + λµH τ + µµH τ ) > 0
⇐⇒ (βµH2 − β2µ − β2λ − β2µH − βµT2 − β2µT + β2τ + µH2 τ
+ βλµH − βλµT + βµµH − βµµT − βµH τ + βµT τ + λµτ
+ λµH τ + µµH τ ) < 0, (A.3)
√ > 0 and ℜ0T < 1 =⇒ µ + µT − τ > 0.
with (A.2) following because Σ
Note that the LHS of (A.3) can be rewritten as:
β(τ − µ − µT )(β − µ − µH ) + (β + τ )(λ + µH )(µ + µH − β) + β(µ + µT + λ + µH )(τ − µ − µT ). (A.4)
H T
Since ℜ0 > 1 and ℜ0 < 1 imply that β > µ + µH and τ < µ + µT , we see that (A.4) is negative.
√
Subcase 2.2: Σ is negative.
Then Re(ξ8) < 0. But
√ >0
Re(ξ7) < 0 ⇐⇒ β (µ + µT + λ) + β + (µT − τ ) + Σ
√
⇐⇒ β (µ + µT + λ) + β + (µT − τ ) > −
Σ
⇐⇒ β (µ + µT + µH + λ) + (β − µH ) + (µT − τ ) 2 − Σ > 0
2

⇐⇒ ℜ0T < 1, ℜ0H > 1 [same as Subcase 2.1].

T H
We have shown that ξ1, . . . , ξ8 have negative real parts. Thus the HIV-QDFE is locally asymptotically stable if ℜ0 > 1,
ℜ < 1.
0
Global asymptotic stability of the HIV-QDFE
M ′
Proof of Theorem 3.4.2. We first show that (T +C +C1 +C2 +C1 +C2M ) < 0 if ℜT0 < 1. Let K = T +C +C1 +C2 +C1M
+C2M . Then
′ S H
K = τ (T + C ) + τ (T + C) − (µ + µT )T − (µ + µT + µH )C − (µ + µH )C1
N N
 − (µ + µH + ρ2)C2 − (µ + γ )C1M − µ + ρ2 + γ ρ1 C2
M

ρ1 + ρ 2
= τ ( T + C )(S + H) − (µ + µ )T − (µ + µ + µ )C − (µ + µ ) C − (µ + µ + ρ )C2
T 1 H
N T H H 2

− (µ + γ )C1M − µ + ρ2 + γ ρ1 M
C2

ρ1 + ρ2
≤ τ (T + C) − (µ + µT )T − (µ + µT + µH )C − (µ + µH )C1 − (µ + µH + ρ2)C2

ρ M
− (µ + γ )C1M − µ + ρ2 + γ 1 C2

ρ1 + ρ2
= M
[τ − (µ + µT )] T + [τ − (µ + µT + µH )] C − (µ + µH )C1 − (µ + µH + ρ2)C2 − (µ + γ )C1

− µ + ρ2 + γ ρ1 C2
M

ρ1 + ρ2
≤ ε(T + C)
< 0,
where ε = τ − (µ + µT ) < 0 since ℜT0 < 1.
 A. Mallela et al. / Journal of Computational and Applied Mathematics 307 (2016) 143–161 159

As in the proof of Theorem 3.3.2, we can use the above to show that for any positive K , K → 0. Thus the long-term
behavior of the system can be described by its behavior on the S − H plane [41,42]. The two-dimensional system can be
modeled in the S − H plane by the following limiting equations:
′ S
S = f (S , H ) = Λ − β H − µS
N
′ S
H = g(S, H) = β H − (µ + µH )H.
N
Given the local asymptotic stability of the equilibrium and the boundedness of the system’s trajectories, we can apply the Poincaré–
1
Bendixson theorem [43,44]. Using the Bendixson–Dulac negative criterion, we can rule out a periodic orbit if there exists a C
∂ ∂
function, Ω(S, H), such that ∂ S (Ωf ) + ∂ H (Ωg) does not change sign and is not identically zero on any open set
1 ∂ ∂ − Λ
of the S −H plane. Choosing Ω(S, H) = SH , note that ∂ S (Ωf )+ ∂ H (Ωg) = S 2 H , which does not change sign on any interval.
H
The disease-free equilibrium is a saddle node, because the condition ℜ 0 > 1 implies that only one of the eigenvalues of the
H
Jacobian linearization of the system at the DFE is positive. Since ℜ 0 > 1 implies that the DFE is an unstable saddle with stable
manifold along the S-axis, a solution starting at H(0) = 0 will remain on this stable manifold and converge to the DFE. However, if
H(0) is positive, then the solution is repelled by the DFE and the omega limit set must contain another equilibrium (due to the
absence of periodic orbits). The only available option is the HIV-QDFE. Once the solution gets close to the (locally stable) HIV-
QDFE, the HIV-QDFE will attract the solution. Thus, every solution, for which H(0) is positive, will
H
converge to the HIV-QDFE. Hence, the HIV-QDFE is globally asymptotically stable if ℜ 0 > 1 and ℜT0 < 1.

Adjoint functions of optimality system

1 1
= − N +N − + + N −
N2 + + N2 N2
∗ ∗ ∗ ∗ ∗ ∗ ∗ ∗
(S + T )β C1 C2∗ A1β C1 C ∗ Eβ ES µ (C + T S (C +T λ
λ′A1 2
β
∗
)τ
∗
)τ
∗ ∗ ∗ ∗ ∗ ∗
ET β (C + T )τ S (C + )τ λ
T
2
− N
2 +N − 2
N ∗ ∗
H (C +T
Eβ ES β
∗
H (C
∗ ∗
+ T )τ
∗
λ ET
∗
β λ
∗
)τ
4
2
=− N − N2
+
N2
3 + N2
+
N2 N
2 −
N
1
N2 − N − N 2
+

(S + T )β C1 + ∗+
′A ∗ ∗ ∗ ∗ S ∗(C∗ + T ∗)τ S∗τ
λ 1 A1β C1 ES β λ
∗ ∗
C2 C2

Eβ ET
∗
β µ ∗
S (C + T
∗ ∗
)τ µ S τ
∗
λ
T 2
+ N − N2 + +
N
2 + − N
∗ ∗
H (C +T
ES β
∗ ∗
H τ
∗
H (C + T
∗ ∗
)τ λ Eβ ET
∗
β H τ
∗
λ
∗
)τ
+ + N − + 4
3
= N
2
N
2
3 −N − N
2
N −
N
2
N 2
− N2 − N + N2 1

(S + T )β C1 +
∗ ∗ ∗ ∗ S∗ β ∗ ∗
A ES β S (C + T )τ λ
λ ′ 1 ∗
∗
C2
∗ ∗ ∗ ∗ λ ∗ ∗ µ ∗ µ ∗ ∗ λ
T β ET β S (C +T ES β S β (C + T H (C +T
∗ ∗ ∗
)τ )τ )τ
+ − 3
N − N2 + N2 2+
N
2 − N + +N + A
N
2

T
∗
β ET
∗
β
∗
(C + T )τ
∗
H (C + T
∗ ∗ ∗
)τ λ
4
4 − N − 2 +N − 2
N2 1
= N N +
N 2
+ N −
N2 N −

(S + T )β C1 +
′A ∗ ∗ ∗ ∗ ES ∗ β ∗ ∗ ∗ ∗
λ 1 S β S τ S (C + T )τ λ
∗
C2

T
∗
β ET
∗
β S (C
∗ ∗
+ T )τ
∗ ∗
S τ λ S β
∗
ES β
∗ ∗
H (C + T
∗ ∗
)τ H τ
∗
λ
3
+ N − + − N 2 − N − + − N
N2 N2 N2 N2
 ∗ ∗ ∗ ∗
ET β T β µ H (C +T λ µ µ H∗ τ λ λλ
∗
)τ
−
5
=+ N2 N + + − N2 N+
−
+ H +
N 2
T
−
N
− N
+
4 −
N
2 5 1
N2
∗ ∗ ∗ β ∗ ∗ ∗ ∗ ∗
λ
′A
1
(S + T ) C1 + A1(S + T )β ES∗β S β S (C + T )τ λ
∗ ∗
C2

T
∗
β ET
∗
β
∗ ∗
S (C + T
∗
)τ λ ∗
S β
∗
ES β
)τ λ ∗
H (C + T
∗ ∗

3
+ N − N2 + N2 − N2 + 2
2 −N
N
∗ ∗ ∗
ET β T H (C +T λ + ( u1 + µ + µ + ρ ) λ − ρ λ − u1 λ − A2 µ
∗ ∗ 4
β )τ
2 H 1 5 1 6 7 H
+ − + N
N2 N
 160 = A. Mallela et al. / Journal of Computational and Applied Mathematics 307 (2016) 143–161
2
6
N2 − N − N2 − N + N 1

′ ∗ ∗ ∗ β ∗ ∗ ∗ ∗ ∗ ∗
λ A1 ( S + T ) C1 + A1(S + T )β ES β S β S (C + T )τ λ
∗ ∗
C2

T
∗
β ET
∗
β S (C
∗ ∗
+ T )τ
∗
λ S β
∗
λ ES β
∗
H (C
∗ ∗
+ T )τ
∗

2 3
+ N − + − N − +
N2 N2 N2 N2
ET
∗ ∗ ∗ ∗ ∗
β T β H (C + T )τ λ λ ( µ µ ρ) λ µ
4
7 + N
2 − N + N 2 N2 + 6 u2 + + H + 2 − u2 8− A2 H
= −A3 + − N2
+ N2 1
′ ∗ ∗ ∗ ∗ ∗ ∗
λ γ A1 ( S + T )β C1 + ES S (C +T λ
∗ ∗
C2 β )τ

S (C
∗ ∗
+ T )τ
∗
ET
∗
β λ ∗
H (C + T
∗ ∗
)τ ES β
∗
λ ET
∗
β
∗
H (C + T
∗ ∗
)τ λ
4
+ 2 − 2 2− 2 − 2 3+ 2 + 2
N N N N N N

+ (γ + µ + ρ1) λ7 − ρ1λ8
8 = N2 − N2 + N2 1 + N2 − N2 2
′ ∗ ∗ ∗ ∗ ∗ ∗ ∗ ∗
λ A1(S + T )β C1 + ES S ( +T λ S (C +T ET λ
∗ ∗ ∗ ∗
C2 β C )τ )τ β
− 3 + + + − ρ1
− N2 N2 N2 N2 4 + 8 + 2 ρ1 + ρ 2 + ρ2
∗ ∗
+ T ∗)τ ∗ ∗ ∗ ∗
H (C ES β λ ET ∗β H (C + T )τ λ λ µ ρ γ ρ1 A3 γ ρ1 .

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