An Integrated Approach to Solving HIV/AIDS

Scourge Using Mathematical/Simulation

Techniques


Oyelami
1
B.O, Ale
1
S.O., Onumanyi
1,2
P., Ogidi
3
J.A,
1. National Mathematical Centre, Abuja, Nigeria
2. University of Jos, Jos,Nigeria
3. Abubakar Tafawa Balewa University Bauchi, Nigeria




it isnt that they cant see the solution, it
is that they cant see the problem
-G. U K.Chest in the scandal of father
Blown.
HIV is more destructive than any army,
any conflict, and any weapon of mass
destruction
-US Secretary of State, Collin Powel.




Simulation argument

Simulation argument prepossess that at least of these propositions is true:
1. the human species is very likely to go extinction before reaching a posthuman stage;
2. any posthuman civilization is extremely unlikely to run a significant number of
simulations of their evolutionary history (or variations thereof)
3. we are almost certainly living in a computer simulation. It follows that the belief that
there is a significant charge that we will one day become posthumans who run ancestor-
simulation is false unless we are currently living in a simulation.
-Nick Boston (2005)


Abstract
HIV/AIDS is a hydra-headed problem, which many researchers agreed could be solved
by inter-disciplinary approach. Our idea of integrated approach presupposes that
solution of HIV/AIDS can best be approached from clinical and multi-facet point of
view, that is, through integration of epidemiology, pathology and demography. The
present paper is a technical report on researches we have been conducting on
HIV/AIDS using mathematical modeling/simulation techniques. We used deterministic
and stochastic models to study the growth of HIV/AIDS in some communities in
Nigeria and the cost of placing the victims on life supporting drugs; research were
made on HIV/ AIDS using generic and impulsive models including models on highly
active anti-retroviral drugs (ARDs) and the use of B-Transform developed by Oyelami
and Ale. More over, we studied drug efficacy (potency) on ARDS and HAART using
inhibitors for developing drugs and vaccines against HIV/AIDS. Finally, we use,
CUMSUM and EWMA methods to determine benchmark value for HIV/AIDS
epidemic. We used optimization techniques to determine most efficient utility function
for determining the most cost effective and most efficacious HIV drug.

Keywords:
HIV/AIDS, ARDS, HAART, Impulsive Systems, Control and B-Transform.

1.Introduction
Human immunodeficiency virus (HIV) was first reported in 1984 in USA, Barre-
Sinoussi Montagnier, and his colleagues at the Institute Pasteur, Paris, in 1983 and
gave the name lymphademoparthy associated virus (LAV) same virus now referred to
as HIV-1. Around 1985, another human retrovirus different from HIV-1was
discovered in West Africa and was called HIV-2. HIV-2 remains uncommon outside
West Africa. It is human retrovirus found in green monkeys ([29]). Retroviruses are so
named because their genome encodes unusual enzyme reverse transcriptase that
allows DNA to be transcribe from RNA. Thus, HIV can make copies of its genome,
DNA, in the host such as human help lymphatic genome that is the basis of
infection of HIV ([1]).
+
4
CD

Phylogenetic analysis of the HIV-1 genome has suggested an origin in chimpanzee, in
the case of HIV-2 similarly to the simian immunodeficiency virus SIV genome may
point to an origin in sooty mangabey monkeys, Butchery and consumptions of the bush
meat may be responsible for its transmission ([29]).

Ever since HIV was discovered the world is constantly in the state of pandemonium
and disarray. Over 25.1 million people are already dead from AIDS and over 40.3
million people living with HIV/AIDS (PLWHA). New HIV infection in 2005 is 4.9
million and death due to AIDs in 2005 to be 3.1 million (UNAIDS/WHO, [22]).
Researches have projected that by 2010 HIV/AIDS will reduce average life expectancy
of most South Africans to 30 years ([12]).

The youth comprise about one-forth of the world population and UN Department of
Economics and Social Affairs reported that in 1998 that fifty percent of HIV infection
worldwide is between the age of 15 and 28 (UNAIDS and WHO, [19]).

It is estimated that 11.8 million people between ages 15 and 24 are living with
HIV/AIDS and in African countries, especially sub-Saharan area, 20 percent of
HIV/AIDS are young women. It is undisputable fact that socio-cultural factors have
had greater influence on young people vulnerability to HIV infection.

The origin of HIV from Chimpanzees and monkey as state above is still remained
debatable and really unnecessary as former president of Zambia once said what is
more important than knowing where it is comes from but where it is going. In Nigeria
the first reported case was in 1988 among Commercial Sex Workers (CSW) .The HIV
concern started in 1984 among researchers at the National Institute for Medical
Research Yaba, Lagos.

The first official respond by government of Nigeria to control was in 1988 by setting
up National Expert Advisory Committee on AIDS (NEACA) and later replaced by
2
National AIDS control programme (NACP).

In 1992, the NACP and the National STD were merged. The launching of the National
Policy on HIV/AIDS/ STD Control in Nigerian by the former minister of Health
Professor Debo Adeyemi on the 6
th
of October 1998 at Zaranda Hotel Bauchi during
the 43
rd
National Council on Healths meeting was an important landmark in
HIV/AIDs/STD Control in Nigeria by the government ([11]). There was the NACA,
National Action Committee on AIDS being headed by professor Babatunde
Osotimehin. NACA work closely with Federal Ministries of Health through Honorable
Minister of Health on how to control HIV/AIDS in Nigeria. There are also
collaborators efforts among the NGOs, CBOs and International Organizations to flight
HIV/AIDS in Nigeria.

HIV pandemic in Nigeria as of 2004 stood at 5% sero-positive prevalence in Nigeria
with Over 126 million people (2003 population estimates). That is, to say, over 6
million Nigerian adults are said to have been infected with HIV and by 2010 it is
projected by the USA National Intelligence Agency that between 50 and 75 million
Nigeria will be infected with HIV. The figures given above are estimate. It may be
over or under estimated. Therefore, there is the need to have a very accurate data about
the present status of the disease so as to make projection into the future (NMC Proj
3A). Average life expectancy of Nigerians is 43.4 years at the moment. There is the
fear that HIV will push this value below 43.3 years.

This is even more frightening when we acknowledge that the present national
economic indicator indicated that Nigeria is one of the poorest nations in the world
with per capita < 300 US dollars and human poverty index (1994 ext.) of 40.1.At the
moment Nigerian Human Development Index (HDI) rank 158 and Gross Domestic
Product (GDP) per capita (2003) is US $ 1,050.Clearly this figure is very low when
compared with developed nations in the world (NMC, Proj 2B;UNPD, report 2005).

HIV/AIDS remained most dreaded in the world today, its presence in any community
is the presence of abject poverty, socio- economic deprivation. The presence of social
stigmatization, sorrow, it is a thing that calls for the person to be quarantined by people
and it is like carrying stigma of most unfaithfulness.

2.Motivation for the Research
First postulate of simulation arguments is optimistic that human being will go into
extinction before posthuman stage reached; Powell observed that HIV is the catalyst
that is making mankind to go into extinction. Chest believes that if we can see the
problem then, certainly, the solution would be found .We realized that modeling
/simulations could be exploited to find solution to the multi-facet HIV/AIDs scourge.

3
We have passion for HIV/AIDS Victims; we dont want mankind to go into extinction
as result of HIV/AIDS pandemic. The life support drugs (ARDS and HAART) are
very expensive and beyond the reach of Africans. The per capita incomes of most
African countries and Health per capita spending are very small and could not support
even small percentage of HIV/AIDS victims, hence the victim are doomed to die.

We also know from practice that HIV/AIDS predominantly affects the youth (15-24
years) at this period sexual activity are very higher .The youth contribute to most
productive labour force of a nation. There is Yoruba adage, which says when a
banana wants to give way it replaced itself by buds! AIDS is exterminating the human
buds. There got to be a stop on the pandemic.

AIDS has affected UN millennium goals with rapid increase in orphans population in
the society and high increase in unemployment. Several man-hours are lost as a result
HIV/AIDS illness among workers.

In view of the problems outlined above there is the need to Research into HIV/AIDS
just as the former, US President, Bill Clinton, when he came to Nigeria in 2000,
enjoined Nigerian to conduct research on HIV/AIDS issue and even supported the
country with a grant of 8 million US dollars.

We need to use our knowledge and professional competence to obtain balance
information about HIV/AIDS in all ramifications. We must know how the syndrome
grows and clinical specialties in order to develop drugs or vaccine and to test potency
of existing drugs. We need to make use of mathematical modeling to predict and to
control the scourge and to salvage mankind from extinction as a result of AIDS.

Our research problem is covers wide areas of HIV/AIDS; hence, there is the needs to
sub-divide the area into small units critically study the units. Therefore, our research
falls into three categories:

Demographic impact: This involves studying HIV/AIDS from population dynamic
point of view. This will help the state to stem the growth of the disease and determine
benchmark value for the epidemic. We conducted research on socio-economic status of
the nation, which includes macro-economic factors like human development index,
survalship, and input of HIV/AIDS on UN development goals.

Epidemiological impact: Issue of drug and vaccination against HIV/AIDS and how to
mount surveillance on the disease.

Communication Development Issue: Advocacy, social mobilization and programme
communication. Mathematical model/simulation can be used to test the effectiveness
of any communication development programme used in any community.

Conduct research on HIV/AIDS drugs and vaccine and their potencies using
mathematical modeling or what is often called HIV infection in vivo (see [1]& [23])
and for simulation it is called HIV in Silico ([6])

3.Mathematical modeling / simulation
4
Computer can said to be the midwife of simulation. Simulation in a simple layman
language is the implementation of a model in a computer environment. Simulation has
been defined by C.West Churchman, amongest, several definitions to be X simulates
Y if and only if Y is taken to be an approximate to X, and Schubik defined it to be:
Simulation is therefore essentially a technique that involves setting up a model of a
real life process, and performing computer experiments on the model; in order word,
modeling activities, designing and running of the computer experiment.
In short, simulation is a conglomeration of processes including the use of numerical
techniques for conducting experiments on a digital computer. It involves certain types
of mathematical and logical modeling activities that describe the behavour of a system
over period of time ([39-40]).

Fig 1: Steps needed to simulate a real life problem is represented in the chart below:

Formulation

Formulation of
problems
B
Analysis of
simulation
Design of simulation
experiment
Validation
Development of
computer
program
Evaluatio
n
of model
Estimation of
parameters
(Calibration of model)
Formulation of
mathematical
model
Collection and
processing of data
B

4.Imaging and visualization in HIV/AIDs Research
Computer based simulation in biomedicine (CBSB) represents a rapidly growing area
of Research of late. The CBS combines several interacted disciplines for common
purpose of improving healthcare.

The ultimate purpose CBSB is to create environment that support medical education
and training. For example, through surgery simulation users are allowed to visualize
and rehearse clinical and surgical procedures thereby, ideally providing effective, safe
and reliable means of performing a variety of surgical tasks.

Through CBSB, it allows us to study the anatomy and physiology of complex
5
processes that take place in organisms, through what can be called interactive 3D
graphic and animation. We can study and monitor the movement of substrates in the
cells or intracellular of organisms.

Therefore, simulation allows interposing of computer with medicine for purpose of
visualization of processes in the organism life and allows user interface design and
provided a platform for human-computer interaction.

We do not intend to spend more time discussing CBBS but rather try to see how CBBS
could be used to proffer solution to HIV/AIDs.

This is technical report of some of the researches we have been conducting over the
years on HIV/AIDs. Some are already published and others still in the incubator
waiting hatching.

The first model we will consider is HIV-1 type model used to study the growth of
HIV/AIDs in Bauchi and Gombe states of Nigeria. The idea behind the study of the
growth of HIV-1 in a heterosexual population group in the states and also to compute
cost needed to place the AIDs victims in the states on antiretroviral drugs.

THE MATHEMATICAL MODEL OF THE HIV/AIDS ([13]&[31]])
The following deterministic model can represent the transmission of HIV/AIDS

(1) t) (a,
X
(a)] + (t) [ - =
t
t) (a,
X
+
a
t) (a,
X
Kl
K
Kli
Kl Kl

(2) t) (a,
X
(t) =
t
t) (a,
Y
+
a
t) (a,
Y
Kl Kli
1Kl 1Kl

= t) (a,
Y
(a)] + (a) [ -
Skl
k i

(3) t) (a,
Y
(a) =
t
t) (a,
A
+
a
t) (a,
A
Skl
s
Kl Kl

= t) (a,
A
(a)] + (a) [ -
k K
K


(4) t) (a,
Y
(a) =
t
t) (a,
Y
+
a
t) (a,
Y
1)kl - (s
1 - s
Skl Skl

= t) (a,
Y
(a)] + (a) [ -
Skl
K s

(5) ) ( ) , ( t d t a
A
= C(t)
Kl
n
=1 k

Where
t) (a,
X Kl
Is the number of susceptible people to the HIV disease of sex k and age
a in the activity group of l at time t.

t) (a,
YSkl
Is the number of people infected and infectious but without disease
symptoms and s is the stage (s = 1, 2, 3).

6
t) (a,
AKl
Number of people affected by AIDS at k age group in the l activity
group
k
(a) is the age and sex specific death rate.

s
(a) is the stage specific progressing from s infectious stage to full-blown AIDS.
(t)
Kli
Is the rate per annum at which susceptible acquire the HIV disease.

C(t) is the cost evaluation of the drugs needed to put the AIDS patient on life
supporting drugs.

D(t) is the cost of procurement of the drug.

We used the parameters . 0 . 1 ) ( , 35 . , 2 . = = = a
s sk


3 , 15 , 0 . 1
2 , 15 , 1666 .
1 , 15 , 0 . 1
3 , 2 , 1 , 15 , 5 . 1
) (
= >
= >
= >
= <
=
s a
s a
s a
s a
a
s


To simulate the model using the following algorithm

5.1 Numerical Approximation of the Model ([31])
Let the (t,x) plane be divided into a network of rectangles of sides x = h and t = k by
drawing the set of lines a
i
= a
o
+ ih, i = 0, 1, 2, ..., N - 1 and t
j
= t
o
+ jk, j = 0, 1, 2, ..., N
- 1.

Define
jk) +
t
ih, +
a
(
X
=
X
= t) (a,
X o o kl
kl
j i, kl


jk) +
t
ih, +
a
(
Y
=
Y
= t) (a,
Y o o ikl
ikl
j i, ikl


jk) +
t
ih, +
a
(
Y
=
Y
t) (a,
Y o o ikl
skl
j i, skl
=

jk) +
t
ih, +
a
(
A
=
Y
= t) (a,
A o o
ki
j i,
skl
j i, kl


Thus, if we replace the derivatives in eqs (1-4) by backward difference formula for
Derivative of A, and let

A A
,
Y Y
,
Y Y
,
X X i
ks
j i,
s
i
skl
j i, i
ikl
j i, i
kl
j i,
.

Then equations (1-4) become
(5) (t)
X
] +
X
[ - = (t))
X
- (t)
X
(
k
1
+
dt
(t)
dX
i
k
kl
i 1 - i i
i


7
(6) (t)
Y
]) + [ - (t)
X
= (t))
Y
- (t)
Y
(
k
1
+
dt
(t)
Y
i
k
i
i
kli
1 - i i
i

(7)
Y
] - [ -
Y
(a) = (t)
Y
- (t)
Y
(
k
1
+
dt
(t)
dY
skl
i
k
s
1 - s
i
1) - (s
s
1 - i
s
i
s
i


(8) (t)
A
] + [ -
Y
= (t))
A
- (t)
A
(
k
1
+
dt
(t)
dA
i
k
k
ske
i
s
1 - i i
i

i = 1, 2, ...N-1.

These equations (5-8) are equivalent to the following eqs (9-12), respectively

(9) (t)
b
+ (t)X(t)
C
- =
dt
dX(t)
1 1

(10) (t)
b
+ (t)X(t) + (t)Y(t)
C
- =
dt
dY(t)
2 2

(11) (t)
b
+ (t)A(t) - (t)
Y
(t)
C
- =
dt
(t)
dY
3
s
3
s

(12) (t)
b
- (t)
Y
(t) + (t)A(t)
C
=
dt
dA(t)
4
s
s
4


(13)
(
(
(
(
(
(

=
) t ( k 1 1 0 0 0
0 ) t ( k 1 1 0 0
0 ... ) t ( k 1 1 0
0 ... 0 ) t ( k 1 1
0 ... 0 0 ) t ( hk 1
k
1
) t ( C
i
i
i
i
i
i

(14) + + =
kli
i
X t 1 ) (
1
(15)
k i 2
+ + 1 = (t)
(16)
k s 3
+ + 1 = (t)
(17)

k
k
4
+ + 1 = (t)

X(t)=(X
i
(t)),Y(t)=(Y
i
(t)),A(t)=(A
i
(t))
T
,
Y
s
(t)= ( 1 - 1,2,...N = , ) (t)
Y
T
s
i
Therefore the difference schemes generated from (9-17) couple with (1,0) Pades
approximation ([31]) are:
(18)
H
+
X
) (s)ds
C
- (I
b
=
X j j
-1
1
k
o
1
k 1 + j

8
(19)
N
+
Y
) (s)ds
C
- (1
b
=
Y j j
-1
2
k
o
2
k 1 + j
(20)
M
+
Y
) (s)ds
C
- (I
b
=
Y j
s
j
-1
3
k
o
3
k
s
1 + j
(21) 1 - 0,1,2,...N = j ,
Z
+
A
) (s)ds
C
- (I
b
=
A j j
-1
4
k
o
4
k 1 + j

Where
(22) ds] ) )d (
C
- (s)(I
b
[ ) (s)ds
C
- (I =
H
-1
1
k
o
1
j
o
-1
1
j
o
j


(23)

(s)ds)]d
C
- (s)ds(I
b
+
H
(s) [( + ) (s)ds
C
- (I =
N 2
o
2 j
j
o
-1
2
j
o
j
(24)

(s)ds)]d
C
- (s)ds(I
b
-
N
(s) [- + ) (s)ds
C
- (I =
M 3
o
3 j
j
o
-1
3
j
o
j
(25)

(s)ds]d
C
- (s))ds(I
b
-
M
(s) [( + ) (s)ds
C
- (I =
Z 4
o
4 j
s
j
o
-1
4
j
o
j
(26) 1 - N 1,2,....., = i 1, < ) (s))ds
C
( - (1
i
1 -
i
t
o

Max


The algorithm (iterative scheme) in eqs (18-26) was coded in Pascal and simulated
using the data collected from the old Bauchi State Health Management Board (see
table 1). The results obtained are in table (3&4) and the graphical displays in figures
(1,3-7). The cost implications of placing the HIV/AIDS victims on Zidovudine and
lavirae drugs were computed. The cost implication was #60,000.00
1
or roughly #10
million for the patients from period of diagnosis to death ([9])

Disease
AIDS
Year Under
1 year
5-15
years
15
years
under 1
year
5-15
years
15 &
above
Total

1994

-

-

11

-

-

4

15

1995

1

-

18

-

-

8

26

1996

-

-

21

-

-

10

31



1997

-

-

28

-

-

15

43

Table 1: Bauchi and Gombe States AIDS recurrence cases data for 1994 -
1997

The next simulation methods employed for finding the benchmark value for HIV
epidemic in a give area are the CUMSUM and EWMA methods. Although, there are
other quality control models that can also be used.


9
1
1 US $=#140
6.CUMSUM and EWMA Methods
6.1 CUMSUM is a powerful and reliable tool for detecting small or sudden change in
the mean of a process .The basic concept is that of incorporating all information in the
sequence of the sample value ([24]).

The CUMSUM formula with the observation t, is define as

) , 0 max(
1
+ =
t t
S k z S
where
k is a parameter called the reference or slack value, z is the observation data
A change in mean is signaled if ,h is the parameter called decision parameter
and its range of values leads to decision interval.
h S
t
>

The CUMSUM for decreasing sum is ) , 0 max(
1
+ =
t t
S k z S
The CUMSUM for increasing sum is ) , 0 max(
1
+ =
t t
S z k S
6.2 EWMA Method
The exponential weighted moving average (EWMA) is a statistic for monitoring the
shift in the mean of the data ([25]&[28]).

The EWMA statistic is given as

1
) 1 (

=
t t t t
EWMA z z EWMA
For t=1, 2, 3n, 1 0
Where
t
z is the observation at time t
EWMA
0
is the mean of the data
N is the number of observation to be monitored
Define
2
1
2
|
.
|

\
|

EWMA
S
The control limits of EWMA are
EWMA
kS EWMA UCL + =
0

8 . 2 6 . 2 ,
0
= k kS EWMA LCL
EWMA

UCL and LCL are upper control limit and the lower control limit respectively. We can
use the control limits to determine the benchmark values for the epidemic any value
above UCL is catastrophic and below LCL may not be too dangerous to the
community. Therefore the benchmark values can be can be used for disease
10
survillence, but effort must be intensified to avoid false alarm situation.
To simulate this model we used data obtained from Jos University Teaching Hospital
(JUTH) as follows:



Year Epidemic data(z)
1995 72
1996 103
1997 119
1998 152
1999 165
2000 217
2001 236
2002 249
2003 235

Table 2: Unclassified epidemiological data about HIV/AIDs as obtained from JUTH.


7. A Simple population of CD ([1])
+
4
Hormonal Immune Response and Cell Mediated Response:
Immune system is a set of organs cells and proteins, which responds to the presence of
foreign substance in the body ([49]). The cell-mediated response produces substances
that destroy antibody through cells without production of Hormones and cell-mediated
response produce small lymphocytes called B-cells and T-cells. B-cell produces
antibodies while T-cell for the cell-mediated response are responsible for strong
humeral response

8. Mathematical models from ordinary differential equations (Odes)
David Ho of Almond Diamond Research Institute in USA along with scientists like
Alan and Patrick are one of the scientists who started modelling of HIV-1 type using
Odes. The model used is a kind of logistic model. The search for a model that reflect
the nonlinearity in the dynamics of HIV virus and the most accurate model for
studying HIV growth had led to evolution of several models over the years
([1],[6],[23],[30]&[32]).

Anderson, May and Rowley and other researchers in United Kingdom worked
extensively on Hiv-1 using differential equations as tool.

Alan and Patrick considers the following differential equations
s T d T d
T
T
pT s
dt
dT
T T
>
|
|
.
|

\
|
+ =
max
max
, 1

11
0
T ) 0 ( T =
where
s represents the rate at which new T cells are created in the sources within the body
such as thymus.

P is the maximum proliferations rate and T is the T cell population density at which
proliferations start off. While T is the maximum population of
0
max
T the body can
support
T
d Is the natural death rate per T cells.

The model is simulated subject to stable steady state given by
~
max
2 max
]
4
) ( [
2 T
sp
d p d p
p
T
T
T T
+ + =

If we introduce perturbation term or mass-action term we formulate a Three-
dimensional problem as follows:
kVT T d
T
T
pT s
dt
dT
T

|
|
.
|

\
|
+ =
max
1

*
*
T kVT
dt
dT
=
CV T N
dt
dV
=
*

Where
T are uninfected cells and T* is the

Productivity of infected cells and V is the
population of the virus (see [1]). The above model was simulated using MathCAD
professional 7 software using the Runge-Kutta and Bolsters algorithms and result
obtained

T
|
|
|
.
|

\
|
=
= = =
= = = = = =
0
0
0
7
0
8
0
6
max
8
0
4 , 10 3 , 10 2
10 2 , 05 . 0 , 01 . , 005 . , 01 . 0 , 01 . 0
v
y
T
x
v x y x
x T c k p s

12

3 - 4
5x10 k 1.638x10 v = = = =
=
=
=
3
10 529 . 8 229 . 378
100 :
100 .. 1 , 0 :
) , 100 , 10 , 0 , ( :
x y T
get we
N
k
D x rfixed z
The result shown above is only that of Runge-Kutta method. Such simulation can be
obtained for several values of T, V and T* for different values of parameters to monitor
the population of the HIV virus and T cells.

9. Mathematical models for HIV/AIDs using Operations Research
9.1 Most Effective utility function
We construct most effective utility function for HIV drug using cost and efficacious
analysis. The problem is a typical max min or min max problems of the utility
function and also exploited the Pyiavskiis algorithm for the finding most efficacious
drug and used three minimization algorithms namely gradient, Newtons conjugate and
quasi-Newtons algorithm to finding most cost-effective drug.
This model is particularly useful in Africa where cost of AR and HAART is very
exorbitant. Most people will prefer a cost effective drug and yet the efficacy of the
drug is very important too. It is advisable to buy the most efficacious drug. The
motivation for this study is to find the most efficacious and most cost effective HIV
drug using optimization technique.
We define efficacy of drugs as in ([32]) as
I
o
x
X
k d
k
1
1
2
+
+ =

Where
d
x
= natural death rate of HIV cells
k
2
= the rate of the inhibition of the immune cells
= initial viral load of HIV cell
I
o
X

Define
ij j j i i j i j i ij i i ij
k e l C h e d e C b C a f + + + + + =
2 2
2
Where

a
i
, b
ij
, d
i
,h
i
,I
j
and k
ij
can be determined whenever the c
i
and e
j
are known using the least
square method.

We obtain that optimal solution for J= n and J=N using Pyiasvskiis algorithm to
obtain most efficacious drug and used the four minization algorithms to determine the
most cost effective drug.

Using max min f (c
i
,c
j
) = f(c*, e*) = f
nN

13

C1 C2 C3 C* Ci
E1 (C1,E1) (C2,E1) (C3,E1) (C*,E1) (Ci,E1)
E2 (C1,E2) (C2,E2) (C3,E2) (C*,E2) (Ci,E2)
E3 (C1,E3) (C2,E3) (C3,E3) (C*,E3) (Ci,E3)
...
E* (C1,E*) (C2,E*) (C3,E*) (C*,E*) (Ci,E*)
Ej (C1,Ej) (C2,Ej) (C3,Ej) (C*,Ej) (Ci,Ej)

Table 3:Cost-Efficacy Matrix
For various values of ARs and HAART with different known costs and efficacies the
optimal values C* and E* can be determined and benchmark values set in the region
where the most cost effective and efficacious drug clustered.

This is the region where the most efficacious drugs and most cost effective drugs are
found which is in fact the optimal solution of the using the stated
algorithms. We are still working in this area; the major problem is that of not laying
hands on clinical tested drugs and their efficacies from hospitals in Nigeria. We hope
in future clinical data would be available to enhance our simulation.
) , ( min
, j i j i
e c f max

10. Impulsive HIV Models
Impulsive differential equations (Ides) describe processes, which changes at fixed or
non-fixed moments in form of jumps ([2-3],[33-36]). As a result, solution of such
equations possesses discontinuities, which are not integrable in the ordinary sense.
This peculiarity makes them not easily accessible to most existing concepts as those in
ordinary differential equations ([3],[33-34]). Population is not a continuous process as
it is often characterized by rapid changes hence it is impulsive. Therefore there is the
need to come-up with model which take care of the shortcomings in odes. Since, the
HIV model, which we will consider, is of population family, there is the need to come
up with impulse analogue of the model.

10.1. Biology of HIV (see [32]&[44]) HIV is RNA virus and HIV-1, in particular, is
by reverse transcription (RT) .HIV has three enzymes, namely protease, reverse
transcriptase and integratese . These enzymes are active in the developmental process
of HIV virus. These enzymes if inhibited would be useful in production of drugs to
reduce viral load of HIV or eliminating the virus completely. HIV through reserve
transcription (RT) produces the DNA copy of RNA genome and integrates it to that of
infectious persons DNA via the enzyme, integratese.

The mechanism of inhibit enzyme is that of blocking vital enzyme(s) in the HIV virus
during developmental stage thereby producing HIV virions that are not infectious. The
search for strategic way of controlling HIV/AIDS viral load through inhibitors has led
to isolation of four inhibitors namely:

Fusion Inhibitors (FI)
Non-nucleoside Reverse Transcriptase Inhibitor (NRTI)
14
Nucleoside Reverse Transcriptase Inhibitor (NRTI)
Protease Inhibitor (PLS)

Many HIV drugs are generically named according to the inhibitor they operated upon.

10.2 HIV-1 growth cycle

Bindu and John ([6]) studied the growth rate of HIV-1 from biochemical reaction
perspective. A global computer simulation for the intercellular growth of HIV-1 on
CD
4
T-lymphocyte was made. The simulation allows combined anti-HIV strategies
with 12 stages of HIV-1 dynamical behaviour for the genome. We will not mention all
the 12 stages but state those vital ones to our study (see fig.2).





Envelop HIV Host RNA

Export via binding
And fission
HIV1-progemy


Reverse
Transcriptase

Gag DNA DNA



.



Nuclear
Import


Transcription
Integratase
Transcription
Provirus
DNA

mRNA
ds mRNA
Fig 2:Diagram showing HIV-1 Developmental processes


B-Transform and application to HIV-1 models
The development of the B-transform and applications to HIV-1 model was in response
to crucial question raised in one of the plenary sections of the international conference
on Differential Equations held 18-23 August, 1994 in Plovdiv, Bulgaria .The question
raised then was is it possible to develop a transform method for the impulsive
systems? We found that the answer is in affirmative and has led to the development of
the B-transform.


We shall not state B-transform explicitly, refer to ([30],[32-33],[37]&[40]) but will
only be applied to HIV models.

15
We consider the impulsive HIV-1 model, which is a modified form in ([30]) taking
consideration the interaction between the HIV-1 virus and the cells.
CD
+
4

The model is herein called model A (see[30]&[32]) and it is given as
t
t N(t)), z(t), (t) f + a) t, p(t)T(t)X( -
t
t) X(a, k
- (t)
N k
- N(t)
k
=
dt
dN(t)
k
2
1

1
3
2


1,2. = k ,
t
t N(t)), z(t), (t, f + a) t, P(t)T(t)X( + N(t)
k
+ (t)
z k
- z(t)
k
=
dt
dz(t)
k
2
6 5 4

t
t N(t)), z(t), (t f + a) X(t,
k
- a) t, P(t)T(t)X( +
t
a) X(t,
)
n
-
n
- (1 =
dt
a) dX(t,
k
2
4 3 2

,
))
t
= (N(t
I
= )
t
= N(t
k 1 k

))
t
(z(
I
= )
t
= z(t
k 2 k

))
t
= t (X(a,
I
= )
t
= t X(a,
k 3 k


Satisfying the strictly increasing condition.

+ =
t
,
t
< ... <
t
<
t
<
t
< 0
k k 2 1 o
lim

And satisfying the initial conditions
t)
a
X = a) X(t, 0, = )
t
= t X(a, ,
z
= o) +
t
z( ,
N
= o) +
t
N(
k o o o o
, (

Where
t)N(a)da (a, f = (t) f (t), f
a
+
a
=
k
i
t
o
i
i
i
n
=1 l
o 3

a
i
is the phase change of HIV virus at stage 1.
N(t) is the population of the immune cells present in the blood plasma
X(t,a) is the population of HIV cells at time t and are at the stage a
i
, l = 1, 2.
n
2
is the probability of the HIV cells to repel the immune cells towards the nodes and
the lymphatic cells.

F(t,a) is furticidity function at time t stage a.
f
i
(t,z (t), N(t)), l = 1, 2 are non-linear functions that accounts for the coexistence
between z(t) and N(t).

k
i
i =1, 2, 4,6 are some relevant rate constants.
16
k
5
is the natural death rate of the HIV cells
T(t) is the target cells
CD
and P(t) is the rate of formation of the virion, which is,
assumes to be time dependent.
+
4

We also consider the impulsive drug model (Model B) as follows:

t
t t)), (X(a, g + z(t)) N(t), (t,
L
+ x(t)
k
= (t) x
k 1 7
1 &
t
t t)), (X(a, g + z(t)) N(t), (t,
L
+ y(t)
k
+ x(t)
k
t y
k
2
2 9 8
= ) ( &
))
t
(x(
I
= )
t
= t x
k 1 k
(
))
t
(y(
I
= )
t
= y(t
k 2 k


+
+
=
k
t

,
t
< ... <
t
<
t
<
t
< o
k
k 2 1 o
lim

Where
x(t) and y(t) denotes the amount of drugs intake at time t periodically into the
gastrointestinal tracks and the apparent volume of distribution (e.g., blood, muscles,
tissue etc) at time t, k
7
and k
9
are some rate constants.

The non-linear function L
i
(t, N(t), z(t)), i = 1, 2 gives account of the contributions of
normal and immune cells such that


t) (a,
X
P(t)T(t) - = t)) (X(a, g
1
1

t) (a,
X
P(t)T(t) - = t)) (X(a, g
2
2


Where
X
1
(a,t) is the HIV cells present in the gastrointestinal tracks and X
2
(a,t) are those
viruses hidden in the tissue and muscle etc.
This model addresses the problem of time dependent proliferation of HIV-1 virus and
target cells as against constant proliferation growth as studied by Alan and Patrick.
There is strong
Indication that the natural death rate of HIV cells may be time dependent. Research
still continues on the veracity of this.
11.Results And Discussions
We note that the available data (table 1) was for the year 1994-1997,our model has
allowed us to extrapolate the projected cases for year 1998-2003.This also gave us
insight to future occurrences of the HIV/AIDS scourges and how to strategically
combat the scourges.
The baseline data we have is for the year1994; the study intends to obtain information
on the incidence of syndrome in 10 years time. Admittedly, to arrest the scourge,
17
several interventions are bound to be introduced to the communities. Therefore, it is
not often easy to obtain information that would span through larger interval without
incorporating intervention parameter to the model.

We are still working on this hoping to announce our findings in the future publications.
Our model can be extended to period beyond year 2003,but the simulations result
obtained must be reconciled with the actual situation report on ground before making
projections to future.

The algorithm for eq (18-26) was run on computer and the result obtained was:


Male

Female Disease
AIDS

Year

Y
Skl


A
Kl


S
Kl


Y
Skl


A
Kl


S
Kl


Total
for aids

1998

121.8

30

273

87.50

17.0

183.00

47

1999

234.7

90

274.00

175.0

21.0

188.00

114

2000

487.5

380

273.00

350

77

188.05

457

2001

975

390

273.01

700

420

190.00

810

2002

1950

409

273.07

1400

450

193.04

859



2003

3900

656

273.02

2800

610

183.05

1266

Table 4: Computerized result as obtained from the model for 1998 - 2003.


Year
1994

1995

1996

1997

Monthly cost in million


8.33

22.50

17.22

23.889

Annual cost for the individual

99.96

270.00

206.64

286.67

18
Overall cost 150 270.00 310.00 430.00
Table 5: Cost evaluation for drug therapy as obtained from table 1.









Year


1998

1999

2000

2001

2002

2003

Monthly Cost


26.11


63.33


253.89


450.00


477.22


703.33

Annual Cost


313.32


759.96


3046.68


54.00


5726.64


8439.96

Overall Cost


470


1114


4570


8010


8590


12660

Table 6: Cost evaluation for drug therapy as obtained from Table 2.

The results obtained for the model, show that AIDs progressively increases with years
and very endemic for ages of 15 where it is observed that the demand for sex is higher
at this age group especially males. Most research findings advocated that HIV
preponderances are within the age bracket of 14-24 years. The result we obtained from
the simulation is the re-echo of basic established fact in spread HIV in a community.
Furthermore, from the simulation, as the 3D plot shows, Aids is endemic for males
than female in that communities, since AM is exceedingly higher than AF.The reason
for this may be that women are forbidden in the communities to engage in commercial
sex hawking and indiscrimate sex with men against men who are sexually loose in the
states under study.
The simulated result also suggests that the steady increase in the population of
HIV/AIDs as time progress and the overall budge allocation of the state is not
sufficient enough to support the population AIDs victims (<1% of the states
populations)
Therefore, it calls for rapid respond (intervention) to combat the growth of the
HIV/AIDs in the states.
Fig.1 shows how cumulative effect of Aids in the states is
increasing with time from 1998 to 2003.Fig.2,on the other
hand,show how the population of both infectious,susceptibles
and Aids male victims is higher than female ones in the
19
states.

Ti me(years)
1998 1999 2000 2001 2002 2003
0
200
400
600
800
1000
1200
1400
Fi g.1:Cummulative Effect of AIDS for the States from 1998-2003

YM AM SM YF AF SF
0
500
1000
1500
2000
2500
3000
3500
4000
3900 3468.5556
3037.1111 2605.6667
2174.2222 1742.7778
1311.3333 879.88889
448.44444 17
Fig.2:YSA patients'plot obtained from Table 3.
20
MC AC OC
0
2000
4000
6000
8000
10000
12000
14000
12660 11254.259
9848.5178 8442.7767
7037.0356 5631.2944
4225.5533 2819.8122
1414.0711 8.33
Fig.3:Drug Administration contour

0
500
1000
1500
Populatio
n of AIDS
patients
1994 1998 2002
Year
Fig 4:The recurent case of AIDS
from 1994-2003
3-D Column 3
3-D Column 2
3-D Column 1
Fig.3 shows that the cost of placing the HIV patient and HAART
whether monthly (MC), Annually (AC) or Overall Cost (OC) is
very high. Hence, control of the scourge is the strategic way
of combating the scourge.






21
1998 1999 2000 2001 2002 2003
0
500
1000
1500
2000
2500
3000
Yskl Akl Skl
Populati on of Female AIDS Pati ents
Fig.5: 3D plot for AIDS disease obtained from Table 3

Fig.5 shows that the population of the infectious males is
higher than the susceptible HIV male persons.

1998 1999 2000 2001 2002 2003
0
500
1000
1500
2000
2500
3000
3500
4000
Yskl Akl Skl
Populati on of Male AIDS Pati ents
Fig .6:3D plot for the AIDS disease obtained from table3

The CUMSUM and EWMA simulation gives the following result:

Table 7:CUMSUM and EWMA computations
Year Epidemic data (z) CUMSUM EWMA
1995 72 72 147
1996 103 175 136
1997 119 294 131.8
1998 152 446 136.9
1999 165 611 143.9
2000 217 828 162.2
22
2001 236 1064 180.7
2002 249 1313 197.8
2003 235 1548 199.8

38 . 0 =
EWMA
S
UCL=180.0
LCL =164.0




Exponentially Weighted Moving Average (EWMA) Chart
190
UCL
CUMSUM for reported cases of AIDs in a city in Nigerian hospital
180
Reported AIDS cases in a given hospital in
Nigeria
170
160
EWMA UCL
150
140
LCL
130
1
120
LCL
2 3 4 5 6 7 8
YEAR(199
5-2003)

Fig.8: Quality control chart
From fig.7, UCL=180 and LCL=164.These values can be taken to be the benchmark
value for HIV/AIDs for start and effort to put the scourge in control within the
benchmarks should be intensified.

Application of the B-transform to model A&B yielded:

< <

< <

+ + +

=
+ + +

=
t t t
k
q t
t t t
k
q t
t x I e g L y
q k
q
q y
t x I e g L x
q k
q
q x
k
k
0 0
0 0
)) ( ( ) (
1
) (
)) ( ( ) (
1
) (
2
/
_
2
_
2 0
8
1
/
_
1
_
1 0
7

Where
23

= = =
=
0 0
/ /
_
0
/
_
2 , 1 , ) , ( ) ( ) ( )) , ( (
)) ( ), ( , (
i ds e s a X s T s p ds e s a X g g
and
ds e s z s N s L L
q s
i
q s
i i
q s
i i

Applying the inverse B-transform to the above equations, we get

=
=
i v
i v
q
q
s
i i
i i
dq e a q X
i
a t
Where
ds a s s T s p g B
)
1
(
0
_
1
) , (
2
1
) , (
) , ( ) ( ) ( ) (

< <

+ + + = =
0 0
/
0
1
0 0
7
)) ( ( ) , ( ) , ( ) ( ) ( )) ( ), ( , (
2
1
) ( )) ( (
t t t
k k
q s
i
t k
t x I t t ds a s s T s p ds e s z s N s L
i
x e t x q x B

Where

+
=
0
/
2
1
) , ( dq e
i
t t
tq q t
k
k

For perfect protease inhibitor ([1]) advocated that

ct I I
i
e X a t X

=
0
) , (
That is, should be declining exponentially for given initial viral load . c
being the clearance rate. We also discovered that under impulsive regime, for protease
inhibitor, Alan and Pearsons exponential decline in the HIV viral load is attained for a
variable proliferation rate of the virion and the target cells, and found that must be
such that
) , ( t a X
I
i
I
X
0
2
f
. ] ) 2 ( ) ( ) ( [ )) ( ), ( , (
0 3 2 4 2
ct I
e X c n n t T t p k t N t z t f

=
We concluded (see [32]) that It is interesting to note; however that it does not depend
on the population of . This is very interesting under the application of
protease inhibitor; the influence of the coexistence function becomes negligible as the
treatment increases since will vanished. The proper control of
) ( ) ( t N t z and
ct I
o
e X

3
I and will
reduce the growth of to manageable size, which is not necessary, since are
N
i
X
N
i
X
24
non-infectious.


The efficacy of the drug can be determined from


I
x
X
k d
k efficacy
I
0
2
1
1
+
+ = =
For complete eradication of the HIV virus in the blood plasma, semen, tissue and
muscle the treatment must proceed for the long period time provided there is no case
of cardiovascular problem often associated with prolong use of AR and HAART
drugs. Some scientists advocated two to there years treatment period.
Conclusion
HIV/AIDs is on increase daily and collective effort must be intensified to curb the
scourge an integrated approach is hereby recommended as a strategic way of
combating HIV/AIDs in any community. These involved mobilization oh human and
financial resources to stem the growth of HIV/AIDs that is almost making mankind
extinct. There other researchers should also explore several stochastic models that can
be exploited to model HIV/AIDs this.
Acknowledgements
The researchers are grateful the following institutions for sponsor to attend conference at home and
abroad:
National Mathematical Centre, Abuja,Nigeria.
Abubakar Tafawa Balewa University,Bauchi,Nigeria.
University of Jos.Jos,Nigeria.
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[37] Oyelami B.O., S.O. Ale: Applications of B- transform to fish- Hyacinth model. International Journal of
Education Science and Technology. Vol.33.No4, 565-573.

[38] Oyelami B.O.Manjak N. H., Ogidi J.A. and Mustapha A.M.
Stability Property of some neural firing model using Lyapunov function. Journal of League of
Researchers in Nigeria (Jolorn), vol.4.No.1, 2003,44-158.


[39] Oyelami B.O. and Asere A.A . Mathematical modelling: An Application to corrosion in a petroleum
industry. Proceeding of National Mathematical Centre workshop on mathematical modelling of
environmental problems.vol.6,2004, 48-67.

[40] Oyelami B.O.and Sam O.Ale
Mathematical modelling of the exploitations of biological resources in forestry and fishery. Proceeding
of National Mathematical Centre workshop on mathematical modelling of environmental
problems.vol.6, 2004,1-29.

[41] Oyelami B.O., Ale S.O.and Sesay M.S.
Impulsive Cone value integrodifferential and differential inequalities. Electronic Journal of Differential
Equations vol.2005 (2005) No.66, pp.1-14,

[42] Oyelami B.O.
HIV/AIDS Transmission. Mathematical Centre Monthly.Vol.1.no.4, 2004,8-11.

[43] Oyelami B.O.
Mathematical Modelling: A Strategic way to combat HIV-1.Mathematical Centre Monthly vol.1, No.3,
2004,4-5.

[44] Oyelami B.O.
HIV/AIDS Transmission II: Mathematical illustration of HIV Spread. Mathematical Centre
Monthly.Vol.1, No.5, 2005,6-11.

[45] Oyelami B.O.
Towards A Mathematicalised National Planning for Nigeria. Mathematical Centre Monthly, vol.2,
No.6, 2005,2-4.

[46] Oyelami. B.O.
Supporting the youth to outsmart HIV/AIDs Mathematical Centre Monthly, vol.2, No.9/10,2005,13-16.

[47] Philip, M., Riadh, Z.and Guy C. Basic Patterns in National Health Expenditure. Bulletin of the World
Health Organization, 20(2), 2002.


[48] Staneeki, K. Focus Dialogue on HIV/AIDS and Youth. A paper presented at the 13
th
International
Conference on AIDS, Durban, South Africa, July 9 - 14, 2000.
[49] Stephen J.Merrill
Limit cycles in a model of B-cell Stimulation in
Modeling and differential equations in biology,edited by T.A.Burton.Lecture notes in Pure and Applied
Mathematics.Vol.58,Marcel Dekker,Inc.,Madison,New York.



[50] UNFPA: State of the World population 2002, population, poverty and Global Development Goals the
Way Ahead.
Http://www.unfpa.org/swp/2002/english/ch8/index.htm

[51] UNFPA: Expert Plan Reproductive Health Response as HIV/Compound Food Crisis in South Africa.
http://www.nfpa.org/news/news.cfm/ID=185


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