This document discusses the interactions between HIV and malaria. It begins by introducing the topic and noting that the high fever found in immunosuppressed HIV patients can lead to missed malaria diagnoses. Several studies are then summarized that show HIV negatively impacts the body's ability to develop immunity and produce antibodies against malaria. The document continues by discussing how malaria may increase HIV viral load and transmission risk. It notes that the greatest interaction occurs when one disease is highly prevalent and the other is low. The implications for treatment are that malaria must be diagnosed and treated in HIV patients to control viral load. In areas of high malaria and HIV, the diseases have less impact on mortality. Overall, the document examines the bidirectional relationship between the two diseases.

1. Issued in the interest of the medical profession by Shelys Pharmaceuticals Limited Vol
HIV AND MALARIA - COEXISTENCE
INTRODUCTION
The aim in presenting this review
consist of describing the interac-tions
between the two diseases,
trying to explain the possible
mechanisms, and also describing
the implications for treatment and
prevention. Where malaria is com-mon,
the high incidence of fever
found among immunosuppressed
adults as in HIV patients may lead
to missed diagnosis of malaria for
other OIs. Parasite density and
CD4 cell count are independent
risk factors for the fever of malar-ia
present in HIV +ve patients.
Apart from this is the status of
immunological capability to handle
both the infections. Quite a lot of
studies have been directed to find
out if HIV impacts the capability of
the human body to fight against
malaria.
In the 80s, cross-sectional stud-ies
to determine the serological
response to malaria in HIV-1
infected populations as compared
to control populations in regions of
high malaria transmission showed
startling differences. One particu-lar
study group consisted of 66
hospitalized patients with clinical
acquired immunodeficiency syn-drome
(AIDS) and 70 trauma
patients without clinical AIDS
(controls). Mean optical densities
of antibody produced against
RESA-4, RESA-8, RESA-11,
(PNAN)5 and (NAAG)5 synthetic
peptides of Plasmodium falci-parum
were compared between
HIV-1 seropositive and HIV-1
seronegative patients using non-parametric
statistics. HIV-1
seropositive patients with clinical
AIDS had significantly less anti-body
to the synthetic P. falciparum
ring stage peptide, RESA-8 (P =
0.001), than a comparable group of
seronegative patients. Antibody
levels were also low for the other
ring stage peptides, RESA-4 (P =
0.024) and RESA-11 (P = 0.024).
Although not statistically signifi-cant,
antibody levels among the
HIV-1 seropositive trauma patients
were higher than among the HIV-1
seronegative trauma patients. The
assumption was that during HIV-1
infection, a polyclonal B cell acti-vation
may occur as noted in the
HIV-1 seropositive trauma
patients, but with increased
immunosuppression in advanced
clinical AIDS. Consequently, B cell
stimulation appears to be dimin-ished
resulting in decreased pro-duction
of malaria antibody1.
Some studies have described dif-ferent
and variable results related
with the interactions of HIV and
malaria, especially malaria pro-duced
by Plasmodium falciparum
as is seen in Africa. A very clear
image of these 2 conditions will
merge when we perceive them as
"2 elephants colliding". By this, it
refers to the clear effect on mor-tality
of both of them, although the
evidence of these suspected inter-
FOREWORD
Science is a constantly evolv-ing
subject.Nowhere is this
moreevident than in stud-ieswith
HIV, where a greatdeal
of understandinghas emerged
in the past 2 decades.
Compounding the problem of
HIV in Africais malaria and
thepresence of bothtogether can
be spelt asdouble trouble. Why
soand what can be doneabout
it? Answeringthese questions
andassisting the clinicians
inthier fight to conquer and-control
them is this
update.
Dr. B. K. Iyer
Consulting editor
Shelys Pharmaceuticals
1

2. actions has not been shown until
recent studies. In Africa, the expo-sure
to malaria occurs repeatedly
and people acquire an incomplete
immunity (semi-immune status),
which means that malaria disease
becomes very rare and severe
malaria is almost absent in adult-hood,
but the malaria infection
remains. This semi-immune sta-tus
is reached through years of
repeated exposure to the parasite,
so children are non-immune and
have multiple episodes of sympto-matic
and severe malaria. The age
at which semi-immunity is
reached cannot be precisely estab-lished,
but it is clear that this age
is earlier in areas with higher
intensity of malaria. Among adults,
there is a special group that is
susceptible to malaria infection -
pregnant women, mainly in primi-gravidae
ones, because of the abil-ity
of the placenta to sequester
parasites that express new anti-gens.
IMPACT OF MALARIA ON HIV
Blood transfusions for anemia
secondary to malaria in areas of
high endemicity have been
described as a transmitter of HIV
infection. This is important in
young children in these areas. In
vitro studies related to the influ-ence
of malaria on HIV infection
are not conclusive. They have
described an increase in HIV repli-cation
when exposed to malaria
antigens related with production of
tumor necrosis factor alpha (TNF-alpha).
Short stimulation with
malaria antigens upregulated the
expression of CCR5 but not CXCR4,
but long stimulation upregulated
CCR5 through the production of
interferon gamma , which in turn
blocked HIV replication. On the
other hand, it has been shown that
malaria antigens activate
mononuclear cells, making them
more susceptible to HIV infection
and facilitating the replication of
the virus and a consequent
increase in viral load. Malaria also
produces a reversible decrease of
CD4 cells. This reversibility has
also been demonstrated in
patients with HIV infection.
When extrapolating the impact of
these results, the changes of viral
load described here could reduce
the survival time of untreated HIV
patients by one year, and HIV
transmission could be increased
by 50% during the time of higher
viral load2.
These findings have important
consequences on HIV transmis-sion
coinciding with malaria febrile
episodes and for some weeks after
them, and on the necessity for
adequate malaria treatment to
achieve HIV viral loads similar to
previous states.These results have
important implications for practi-cal
purposes: malaria must be dis-counted
before taking any thera-peutic
decision in HIV-infected
patients, and must be taken into
account in the follow-up of
patients with antiviral therapy in
the malaria areas of Africa.
A long-term, large cohort study
has investigated the effect of
malaria on HIV mortality3. No sig-nificant
relation was found
between level of parasitemia or
clinical malaria and mortality.
Mortality rates in HIV-seronegative
patients were also not associated
with malaria episodes. The effect
of malaria on mortality was not
significantly different between
patients who were HIV seropositive
and HIV seronegative.
LEARNINGS FROM THE
STUDIES
Various studies have now conclu-sively
shown that the influence of
one disease on the other is higher
when the independent prevalence
of one of them is very high and the
other is very low, but when both
prevalences are very high the
interaction does not affect them
significantly. This means that
areas with high HIV endemicity and
low or unstable malaria preva-lence,
and areas with high malaria
transmission and low HIV preva-lence
are the most at risk for the
interaction. These results are of
important epidemiologic relevance
as the treatment of malaria in HIV
infected patients4.
HIV INFLUENCE ON MALARIA
As described above, the impact of
HIV on malaria immunity differs
depending on the degree of
acquired immunity against the
parasite and the timing of the coin-fection.
It has been proposed that
if coinfection occurs simultane-ously,
there could be a nonspecific
effect on parasite development or
against immune-mediated malar-ia
pathology, and later on, if
malaria is not treated, the develop-ment
of malaria immuntiy could be
affected. The influence of HIV
infection can also affect the
acquired antimalarial immunity.
The proposed mechanisms are the
decreased number of CD4 cells
considered as essential for the
development of this immunity, but
also the loss of memory T-cells
induced by viral infection5.
Infection with HIV has also been
related with malaria treatment
failure, secondarily to new malaria
infections. The explanation of
these findings can be found in a
2

3. weaker cell-mediated response
that would be responsible for elim-inating
parasites from liver cells,
hindering their developing in this
liver stage.
When analysis of the risk factors
associated with severe malaria
were done in comparison with
nonsevere malaria; a significant
association was noticed in
HIVinfection, with those nonim-mune
for malaria having higher
parasitemia and higher WBC
counts.
TREATMENT IMPLICATIONS
Related with the response to
treatment, it seems logical to con-sider
that malaria treatment
would be less effective to eliminate
malaria parasites in those patients
coinfected with HIV, as the
immune system is necessary to
attain this elimination.
For adults (older than 18 years)
the global risk of clinical treatment
failure was more than 3-fold high-er
in those HIV-infected. This dif-ference
did not exist for children.
When analyzing separately
recrudescence risk or new infec-tions
risk, the difference in
recrudescence was not significant
between the 2 groups, but the risk
of new infection was more than 6-
times higher in the
HIV-infected adults. These
results strongly suggest that the
mechanism by which HIV affects
malaria must be the reversion of
acquired antimalarial immunity.
Therefore, in children in whom
immunity has not been completely
developed, HIV infection does not
alter the incidence of malaria.
Other studies have been devel-oped
obtaining similar results:
z Prolongation in time for para-site
clearance in HIVinfected
patients when using
artemisinin in Ethiopia;
z Significantly higher hazard
ratios for recurrent parasitemia
in coinfected patients with sul-fadoxine-
pyrimethamine in
Malawi; and also
z Significantly higher hazard
ratios for treatment failure due
to reinfection in HIV infected
patients treated with chloro-quine,
sulfadoxine-pyrimethamine,
amodiaquine,
or artesunate in Uganda 6.
Interactions between antimalari-als
and antiretrovirals
Protease inhibitors alter the plas-modium-
host interactions,
decreasing the pathophysiology of
the parasite or altering the host
defense against it. Nevirapine,
ritonavir, and saquinavir were
studied in relation with their capa-bility
of decreasing the expression
of CD36 receptor in the surface of
macrophages and C32 cells. This
receptor is implicated in phenom-ena
of cytoadherence and phago-cytosis
of the parasitized erythro-cytes,
and it has been described
that antiretrovirals decrease CD36
surface concentrations. The 2 pro-tease
inhibitors reduced the CD36
expression and thus the cytoad-herence
and the phagocytosis of
parasitized erythrocytes; but, this
change was not induced by nevi-rapine.
A recent study has been
published demonstrating an anti-parasitic
effect and inhibiting the
growth of malaria parasites, of
sera from patients taking protease
inhibtors. Interactions with signifi-cant
clinical relevance can result
from the use of antiretroviral
drugs and malaria treatment.
Some of them are of clinical
importance and clinicians need to
be aware about them.
CONCLUSION
The difficulties in the fight
against malaria and HIV are well
known when health programs are
implemented in disadvantaged
areas, but a better knowledge of
the diseases and their implications
are perhaps a good starting point
in the search for a better outcome.
REFERENCES
1 Fred Wabwire-Mangen et al,
Immunological Effects of HIV-1
Infection on the Humoral
Response to Malaria in an
African Population, Am. J. Trop.
Med. Hyg., 41(5), 1989, pp. 504-
511.
2 Withworth J, Hewitt K. Effect of
malaria on HIV-1 progression
and transmission. Lancet
2005;365:196-7.
3 Quigley M, Hewitt K, Mayanja B,
et al. The effect of malaria on
mortality in a cohort of HIV-infected
Ugandan adults. Trop
Med Intern Health 2005;10:894-
900.
4 Maria Dolores Herrero, et al.
HIV and malaria. AIDS Reviews
2007;9: 88-98.
5 Rénia L, Potter S. Coinfection of
malaria with HIV: an immuno-logical
perspective. Parasit
Immunol 2006;28:589-95.
6 Hewitt K, Steketee R, Mwapasa
V, et al. Interactions between
HIV and malaria in non-preg-nant
adults: evidence and
implications. AIDS 2006;
20:1993-2004.
3

4. Laughtter Challllenge
Patient: Doctor, I have problem, I feel unhealthy and
Produced and presented by Shely’s Pharmaceuticals, New Bagamoya road, P.O. Box 3016,
Dar es Salaam, Tanzania and edited on their behalf by Dr. B.K. Iyer, Consulting clinical co-ordinator.
Email: iyerbk@gmail.com
depressed.
Doctor: You should cut down on drinks.
Patient: I don't touch a drop.
Doctor: You should cut down on smoking.
Patient: I don't smoke.
Doctor: You should stop taking drugs.
Patient: I don't do drugs.
Doctor: You should cut down on womanizing.
Patient: Haven't touched a woman in my life.
Doctor: In that case, get yourself a drink, learn to
smoke, do some drugs, and find a couple of
girlfriends.
Mary: My daughter believes in preventative medi-cine,
doctor.
Doctor: Oh, really?
Mary: Yes, she tries to prevent me from making her
take it!