Challenges in the Prevention, Diagnosis, and Treatment of

Malaria in Human Immunodeficiency Virus-Infected Adults

in Sub-Saharan Africa
Paula E. Brentlinger, MD, MPH; Christopher B. Behrens, MD; James G. Kublin, MD, MPH
Arch Intern Med. 2007;167(17):1827-1836.
ABSTRACT

Background Many countries in sub-Saharan Africa currently

report high prevalences of
both human immunodeficiency virus

(HIV) and Plasmodium falciparum malaria. The
likelihood of HIV-malaria

coinfection may affect clinical management of patients. The

extent to which standard clinical guidelines address HIV-malaria

coinfection is unclear.


Methods We reviewed standard World Health Organization

and other guidelines for
diagnosis and treatment of malaria

and/or HIV-related illness. We also searched
PubMed (1990 to

present) for literature on HIV-malaria interactions and treatment

of
coinfection. We restricted our review to the situation of

the nonpregnant HIV-infected
adult.


Results We found only 6 articles describing the clinical

presentation of HIV-malaria
coinfection in adults. We also identified

10 clinical or laboratory syndromes that are
shared by malaria

and AIDS-related conditions and that might provoke diagnostic

confusion. We identified 12 antimalarial medications whose coadministration

with
antiretrovirals is known or suspected to result in drug-drug

interactions or overlapping
toxicities.


Conclusions Substantial overlap in the clinical and laboratory

characteristics of malaria
and HIV-related syndromes generates

potential difficulties in AIDS staging and in
diagnosis and

management of patients at risk for coinfection. Significant

drug-drug
interactions and overlapping drug toxicity profiles

further complicate concurrent
management of malaria and HIV.

Standard clinical guidelines do not reflect the full
complexity

of the interactions and overlaps between the 2 infections. Clinicians

who
manage HIV-infected patients in malaria-affected regions

should systematically consider
malaria when evaluating patients

with a broad spectrum of symptoms. Further research
is urgently

needed to define best practices for prevention, diagnosis, and

management of
HIV-malaria coinfection in this region.

INTRODUCTION

Plasmodium falciparum and human immunodeficiency virus type

1 (HIV) intersect widely. Each pathogen infects millions annually

in Africa alone (Table 1).
1-2
Coinfection may accelerate the

spread
of both diseases.
3

Jump to Section
WTop
WIntroduction
WResults
WComment
WAuthor information
WReferences

View this table:

[in this window]
[in a new window]
[as a PowerPoint slide]

Table 1. Malaria Incidence and HIV Prevalence in Selected Sub-

Saharan African Countries
a

In our own field experience, the differential diagnosis of malaria

and HIV-related
syndromes has proven challenging, and neither

textbooks nor local guidelines have been
of sufficient help.

Therefore, we conducted a literature review with the primary

aim of
describing the challenges that HIV-malaria coinfection

presents to clinical care. We
focused on P falciparum in the

nonpregnant adult because children, pregnant women,
and patients

with non-P falciparum malaria often require different

approaches to
diagnosis and treatment.
4-6
Because most available

clinical data on HIV-malaria
coinfection were acquired in sub-Saharan

Africa, our discussion will center on this region.


We reviewed and compared World Health Organization (WHO) and

2 other widely used
guidelines (Mdecins sans Frontires;

International Center for AIDS Care and Treatment
Programs) for

management of malaria and AIDS in low-income settings.
7-15
We

also
searched the primary English-language scientific literature

on HIV-malaria coinfection,
using the terms IV, AIDS, 2,,7,,

plasmodium, viral load, CD4, antiretroviral, and
anti2,,7,l,

using the PubMed database for 1990 to the present. We also explored

references cited in articles and guidelines. We categorized

key clinical syndromes on the
basis of internal consensus among

ourselves. We consulted review articles and standard
guidelines

for information on drug toxicities and drug-drug interactions,

but we did not
review the primary pharmacologic literature.



RESULTS


We identified 6 studies describing the clinical presentation

of
acute malaria in HIV-infected adults.
16-21
We also identified

10
syndromes that are shared by malaria and AIDS-related
conditions.

We identified 12 antimalarial medications whose
coadministration

with antiretrovirals is known or suspected to
result in drug-drug

interactions or overlapping toxicities. Relevant
clinical concerns

are summarized in subsequent sections and in
Table 2.




View this table:
[in this window]
[in a new window]
[as a PowerPoint slide]

Table 2. Considerations in Differential Diagnosis: Clinical and/or

Laboratory Findings Shared by Malaria and HIV-Related
Conditions

HIV VIRAL LOAD AND MALARIA

Jump to Section
WTop
WIntroduction
WResults
WComment
WAuthor information
WReferences

Acute malaria elevates HIV viral load significantly, approaching

1 log in some subgroups
and persisting for as long as 8 weeks,

even after effective antimalarial treatment.
22, 45

Potential

mechanisms include increased HIV replication, up-regulation

of HIV coreceptors,
and dendritic cell activation.
46-50

,,7, may increase the risk of IV transmission. Although

increased sexual
transmission of HIV resulting from malaria-related

viral load elevations has not yet been
characterized prospectively,

it is likely to occur.
23-24
The public health impact may be

substantial because of the high prevalence of malaria and the

prolonged nature of
observed HIV viral load elevations.
3
Malaria-associated

immune activation may also
render individuals with malaria more

susceptible to the acquisition of HIV.


CD4 COUNT AND MALARIA
Malaria appears to reduce the CD4 count. One observational study
26
described an
excess decline in CD4 count of approximately 40/L

per year for each episode of acute
malaria in HIV-infected persons.

A prospective study
51
found significant increases in
mean CD4

counts (297 to 447/L) and decreases in the proportion

of patients with a CD4
count less than 200/L (28.7% to

13.2%) after successful malaria treatment in HIV-
infected individuals.

Findings in adults not infected with HIV have been similar.
52

Considerations are as follows:


CD4 count measurement during or shortly after acute 2,,7,

may lead to
misclassification of disease stage and premature

initiation of antiretroviral treatment
(ART). No guideline recommended

postponement of routine CD4 measurements in the
aftermath of

malaria.


,,7,induced declines in CD4 count and elevations in viral

load might also result in
erroneous diagnosis of ART regimen

failure and premature switching to secondline
regimens. However,

no available data describe CD4 and viral load response to acute

malaria in patients taking antiretroviral drugs.


MALARIA INCIDENCE AND SEVERITY IN HIV INFECTION
Early studies of malaria incidence in HIV-infected persons failed

to find significant
interactions, but these studies were thought

to have methodologic limitations.
53-54
More
recent prospective

cohort studies have demonstrated rising malaria incidence as

CD4
counts decline in HIV-infected adults living in regions

of stable malaria transmission.
55-56

The observed increase is

greatest in the lowest CD4 strata. A study in Uganda
documented

an odds ratio of 6.1 for clinical malaria in persons with a

CD4 count less
than 200/L, as compared with those with

a CD4 count of 500/L or more.
56
Increased
malaria severity

has also been observed in HIV-infected persons living in regions

of
unstable malaria transmission.
16-17,57
In a study in South

Africa, the odds ratio for
association of HIV infection and

fatal malaria was 7.5.
16
The incidence of malaria in
HIV-infected

persons is estimated to be higher than that of cryptococcal

disease, invasive
pneumococcal disease, herpes zoster, toxoplasmosis,

and Pneumocystis pneumonia.
58

Considerations are as follows:


The association between 2,,7, and advancing immunosuppression

in the IVinfected
adult is not reflected in current guidelines

for staging of AIDS. Recurrent respiratory tract
infections

and severe bacterial infections are WHO stage 2 and 3 criteria,

respectively,
but recurrent and/or severe malaria are not considered.
7
We are aware of only 1
published study that regarded severe

malaria as an AIDS-defining opportunistic disease
(OD).
59

Increased incidence and severity of 2,,7, infection are likely

to augment the overall
burden of morbidity and mortality in

IVinfected persons. The consequences of malaria
may include

anemia, lost work and school time, chronic neurologic deficits,

and death.
12

Estimated country-specific HIV-related increases

in malaria mortality in sub-Saharan
Africa range from 0.65%

to 114%.
60

requent prescribing of anti2,,7,l medications may increase

the risk of adverse drug
reactions and the difficulty of diagnosing

them. There is increased risk of adverse
reactions to sulfonamides

(eg, sulfadoxine-pyrimethamine) with advancing AIDS.
61
Data

on the pharmacodynamics of antimalarial compounds in adults

with severe malnutrition
or wasting are unavailable, although

data on severely malnourished children suggest that
alterations

in metabolism do occur.
62-63
Adverse reactions to antimalarials

may be
difficult to distinguish from opportunistic infections

(OIs), from adverse reactions to
antiretrovirals, and from the

symptoms of malaria itself.
64
Some overlapping drug
toxicity

profiles that may cause diagnostic confusion are described in

Table 3. However,
few published studies have quantified the

likelihood of adverse effects of antimalarial
medications in

adult patients with AIDS, and one recent review observed that

the
methods used in antimalarial drug trials did not consistently

support rigorous reporting
of adverse drug effects.
73
The safety

of antimalarial regimens for HIV-infected infants
and pregnant

women is even less well established.
74
Suggested guidelines

for
pharmacovigilance in Africa reiterate the need for further

research.
14, 75



View this table:
[in this window]
[in a new window]
[as a PowerPoint slide]

Table 3. Selected Antimalarial, Antiretroviral, and Other

Medications With Overlapping Adverse Effect Profiles

requent prescribing of anti2,,7,l medications may increase

the risk of drugdrug
interactions. For example, because HIV

protease inhibitors inhibit cytochrome P450
enzymes, coadministration

of these agents with halofantrine hydrochloride may result in

cardiotoxic effects. Coadministration of amodiaquine, artesunate,

and efavirenz has
resulted in hepatotoxic effects in healthy

volunteers; significantly impaired metabolism of
amodiaquine

(likely to increase risk of adverse effects) has been observed

in the
presence of efavirenz, saquinavir, tipranavir, and ritonavir

in clinically relevant
concentrations and in individuals with

common polymorphisms in CYP2C8.
71, 76

Conversely, the nonnucleoside

reverse transcriptase inhibitors may compromise the
therapeutic

efficacy of quinine through induction of the cytochrome P450

system. While
the predicted outcomes of some pharmacokinetic

interactions have been described, the
full extent of this problem

is unknown because published data on interactions between
antiretrovirals

and antimalarials-particularly artemisinin-based combination

regimens-
are scarce.
77-78
Indeed, standard WHO guidelines

for conduct of antimalarial drug
efficacy trials suggest exclusion

of patients taking other medications on a long-term
basis.
79
In Table 4, we describe selected drug-drug interactions involving

important
antimalarials, antiretrovirals, and other agents.

Again, the published data seldom
provide quantitative estimates

of risk.




View this table:
[in this window]
[in a new window]
[as a PowerPoint slide]

Table 4. Selected Drug Interactions Involving Antimalarials and

ARVs or Other Selected Medications Commonly Used in the Care
of HIV-Infected Patients in Sub-Saharan Africa

requent prescribing of anti2,,7,l medications may speed the

development of
anti2,,7,l drug resistance.
86-88
Malaria resistance

to preventive co-trimoxazole (a
combination of trimethoprim

and sulfamethoxazole) may also develop, although it has
not

yet been documented in vivo.
85, 89-90

Antiretroviral agents may play a future role in 2,,7, prevention

and treatment. Recent
investigations suggest that some antiretrovirals

may possess antimalarial properties and
may even act synergistically

with antimalarials against P falciparum.
91-96
If so, continued

ART may provide some antimalarial protection for patients whose

co-trimoxazole
prophylaxis is suspended after immune reconstitution

occurs. However, the effectiveness
of ART for long-term malaria

prophylaxis (or treatment) has not yet been established in
clinical

trials.


FEVER
Fever is the most widely recognized manifestation of malaria.

Fever may also be caused
by HIV itself, OI, or adverse drug

reaction. Several studies of the causes of fever in HIV-
infected

persons living in regions of stable malaria transmission have

found that the
majority of episodes of fever are not caused

by malaria.
30, 97-98

Related concerns are as follows:


The common practice of prescribing anti2,,7,ls for all episodes

of fever in regions
where 2,,7, is endemic is likely to lead

to both overtreatment of 2,,7, and
underdiagnosis of other

treatable causes of fever.
11, 38, 99-100
Presumptive malaria

treatment has been justified by the scarcity of clinical laboratory

facilities, the potential
lethality of malaria, and the poor

perceived predictive value of negative results of
malaria smears

in high-prevalence areas. However, WHO now recommends that all

health facilities engaged in HIV/AIDS care be equipped to test

for malaria. The
guidelines we reviewed gave varying recommendations:

one suggested laboratory
confirmation of malaria in patients

with fever and no other identifiable source
11
; another
recommended

presumptive treatment of all fevers with antimalarials in areas

of high-
level malaria transmission.
8
No AIDS-specific guideline

mentioned that asymptomatic
malaria parasitemia may coexist

with other febrile conditions, and that the presence of
malaria

parasitemia therefore does not confirm malaria as the sole source

of a patient's
fever.


ANEMIA
Malaria causes anemia through several mechanisms, including

increased destruction of
infected erythrocytes and postinfection

impairment of erythropoiesis.
101-102
Ten percent
of adults with

severe malaria are reported to have hemoglobin levels of 7 g/dL

or less
on hospital admission overall.
12
Infection with HIV

itself may cause anemia, as do many
OIs and ODs.
32, 103
Finally,

several medications used to treat AIDS and its complications

can cause anemia.
36, 104

Concerns are as follows:


here 2,,7, transmission occurs, the overall burden of anemia

is likely to be greater,
with resultant decreases in work capacity,

increases in maternal mortality, and, perhaps,
faster progression

of IV disease.
105-106
Anemia is an independent predictor of

mortality
in patients with AIDS in both developed-country and

low-income settings.
103, 107

either the absence of parasitemia nor the persistence of anemia

after anti2,,7,l
treatment rules out 2,,7, as a cause of

anemia. Malaria-related anemia can progress
for up to 2 weeks

after clearance of parasitemia.
102
Unexplained anemia unresponsive

to
malaria treatment is now an indicator of stage 3 AIDS,
7
but

no guideline defined the
anticipated time course for hematologic

recovery after a malaria episode. The standard
primary care-oriented

guideline
8
did recommend presumptive treatment for malaria if

otherwise unexplained anemia occurs in a patient at risk for

malaria, and the standard
WHO reference on severe malaria
12
discusses severe malaria-related anemia in detail.


The presence of 2,,7, parasitemia does not rule out other

causes of anemia. The
etiology of anemia is commonly multifactorial.
108
Some,
9, 109
but not all, current
guidelines acknowledge the

difficulty of distinguishing anemia caused by medication
toxicity

(eg, zidovudine) from anemia caused by infection.


RESPIRATORY SYNDROMES
Pulmonary symptoms have been described in 3% to 10% of patients

with P falciparum
malaria.
110
Cough occurs in up to 50% of adults

with malaria, and pulmonary edema
has been called "a grave and

usually fatal manifestation of severe falciparum malaria in

adults."
12, 111
However, cough and/or respiratory distress may

also be signs of OI/OD or
immune reconstitution inflammatory

syndrome.


,,7, is not included in common clinical guidelines or algorithms

that address the
differential diagnosis of respiratory symptoms

in IVinfected persons. Only the
monograph on severe malaria
12
discussed the association between malaria and
respiratory distress

in detail, and no HIV-specific algorithm for diagnosis of respiratory

complaints mentioned malaria. In contrast, there is ample pediatric

literature describing
overlapping presentations of malaria and

pneumonia in children younger than 5
years.
112

GASTROINTESTINAL AND HEPATOBILIARY SIGNS AND SYMPTOMS
Nausea, vomiting, splenomegaly, hepatomegaly, jaundice, abdominal

pain, and
transaminase level elevations have all been reported

in patients with acute malaria.
Similar gastrointestinal signs

and symptoms may be the result of OI/OD, adverse
reactions to

antiretrovirals, or immune reconstitution inflammatory syndrome.


,,7, is not included in common clinical algorithms or guidelines

that address the
differential diagnosis of gastrointestinal

symptoms in IVinfected persons. The standard
monograph on

severe malaria
12
was the only document to describe the association

between gastrointestinal symptoms (eg, vomiting and jaundice)

and malaria in detail.
One other guideline
9
recommended (in

a footnote only) consideration of malaria in
patients with high

fever and abdominal pain. The other documents we reviewed did

not
consider malaria in the differential diagnosis of gastrointestinal

or hepatobiliary
complaints.


NEUROLOGIC SYNDROMES
Neurologic signs and symptoms of malaria include headache, mental

status changes,
coma, and seizures.
43
Headache occurs with acute

malaria episodes in regions of both
stable and unstable transmission;

the more serious syndromes-hallmarks of severe
malaria-occur

(in adults) more frequently in regions where malaria transmission

is
unstable. Most
8-9,11-12
of the guidelines we consulted recommended

consideration of
malaria in the HIV-infected person with severe

neurologic symptoms.


Other concerns are as follows:


Severe cerebral 2,,7, is commonly treated with medications

that may be incompatible
with antiretrovirals, or whose safety

in this context is unknown. Quinine is considered
incompatible

with certain antiretrovirals.
77
Artesunate (usually in combination

with a
second agent) is likely to replace quinine soon for the

treatment of severe malaria, but
no published studies describe

its compatibility with antiretrovirals.
113

Immunosuppression related to IV may render previously immune

adults vulnerable to
severe 2,,7,. The immune response to

malaria is mediated by CD4 cells.
114-115
Thus,
adults who reside

in areas of stable transmission may lose their acquired immunity

with
advancing HIV-related immunosuppression. Patients in AIDS

stages 3 and 4 who are not
taking co-trimoxazole prophylaxis,

are not using insecticide-treated bed nets, and do not
have

reliable access to medical attention would presumably be at

highest risk. Early
studies that failed to discover associations

between cerebral malaria and HIV in regions
of stable transmission

did not control for HIV disease stage.
116-117

LACTIC ACIDOSIS
Lactic acidosis is a complication of severe malaria and a poor

prognostic indicator.
12, 118

o IVspecific guideline mentioned that the differential diagnosis

of lactic acidosis
should include severe 2,,7,. Lactic acidosis

was described only in the standard
monograph on severe malaria,
12
although the primary-care guideline
8
mentioned that
rapid, deep

respirations could be a sign of malaria. The HIV-specific guidelines
9-10,109
mentioned lactic acidosis only in the context of adverse drug

reaction. Widespread use of
stavudine in resource-limited settings

increases the likelihood that this potentially fatal
complication

will occur.
39-40

IMPAIRED RESPONSE TO ANTIMALARIAL TREATMENT IN HIV-INFECTED
PATIENTS
In one recent Kenyan study,
18
87.7% of adults not infected with

HIV had an adequate
clinical and parasitologic response to sulfadoxine-pyrimethamine

monotherapy at 28
days, compared with only 68.0% of HIV-infected

patients with a CD4 count less than
200/L (P < .001).

Molecular methods were used to confirm that approximately one-
third

of the treatment failures were caused by reinfection. A study

in Zambia observed
similar outcomes, but without quite achieving

statistical significance.
19

Thus, IVinfected patients with acute 2,,7, may require increased

posttreatment
vigilance to detect treatment failure. Higher

likelihood of treatment failure also implies
greater exposure

of HIV-infected persons to second-line and even third-line
antimalarials,

with the attendant risks of drug interaction or adverse reaction.

Because
exposure to malaria is so frequent in regions of intense

perennial transmission, the
existing WHO recommendation that

patients be screened and treated for malaria
109

before starting

ART does not address this question. The increases in HIV viral

load
attendant to malaria may also be sustained for longer periods

in the presence of
decreased antimalarial efficacy, resulting

in increased transmission of HIV.
3


COMMENT


Our review of existing guidelines and pertinent literature leads

us
to conclude that the HIV-infected patient residing where

malaria
is endemic or epidemic may be at substantial risk of

misdiagnosis
and mismanagement for 5 reasons. First, the heterogeneous

clinical manifestations of both malaria and HIV-related disease

render clinical decision making difficult even for experienced

clinicians. Second, both asymptomatic and symptomatic malaria

may occur concurrently with OIs and/or adverse drug reactions,

thus complicating
diagnosis and management. Third, the nonoverlapping

and oversimplified nature of some
vertical guidelines is likely

to lead to errors of commission (eg, overtreatment of malaria

in febrile patients) and omission (eg, failure to consider malaria

in the patient with
respiratory or gastrointestinal symptoms

or lactic acidosis). Fourth, the published
literature is as

yet inadequate to guide clinicians and patients who wish to

estimate the
risks of concurrent administration of antimalarials

and antiretrovirals (or other agents).
Finally, inadequate access

to clinical laboratory facilities places patients with AIDS

at high
risk of receiving antimalarial medications presumptively,

even when their symptoms are
caused by other entities.


We concur with WHO's recommendations for harmonizing and improving

HIV-malaria
policy,
14
but we would propose amplifying and/or

modifying them as follows.


1. Intensified efforts to reduce malaria transmission should be

conducted where
both malaria and HIV infection are prevalent.

Insecticide-treated bed nets should
be made widely available

at the lowest possible cost (preferably none).
119

2. Malaria-HIV

research priorities should include the following:


4 Description

of longitudinal response of CD4 count and HIV viral

load to

malaria infection in persons taking highly active ART


4 Description

of the clinical effectiveness of antiretrovirals

for prevention

and/or treatment of P falciparum infection


4 Assessment

of the

effectiveness, safety, and pharmacodynamics

of
artemisinin-based

combination therapy when coadministered

with
antiretrovirals

and other medications commonly used in

AIDS care


4 Description

of antimalarial pharmacodynamics in malnourished

and/or
wasted

HIV-infected persons


4 Longitudinal surveillance of malaria

susceptibility to preventive

co-
trimoxazole


4 Description of

clinical presentation of acute malaria in HIV-infected

persons

(stratified by CD4 count and/or clinical disease stage),

in

regions
of stable and unstable transmission, with a particular

focus on syndromes
other than acute fever



3. Standard vertical

guidelines for prevention, diagnosis, and

treatment of HIV and

malaria should be systematically harmonized,

so that patients

receive adequate
attention regardless of whether

the attending

clinician was trained by the local
malaria or

HIV/AIDS program.

Jump to Section
WTop
WIntroduction
WResults
WComment
WAuthor information
WReferences

4. Guidelines for diagnosis and management of common clinical

syndromes

in HIV-
infected persons should be rigorously validated,

with

particular attention to the
role of laboratory testing

for malaria.


5. Persons infected with HIV who are taking highly

active ART or

other long-term
medication regimens should be

urged to seek

care at laboratory-equipped health
facilities

for malarialike

symptoms, rather than self-medicating, whenever

feasible; lower-level

health units must be systematically reinforced

to expand
capacity

for acute care of patients with AIDS.


6. Future

iterations of the WHO staging criteria should clarify

the association

between
recurrent malaria, severe malaria, anemia,

clinical

disease stage, and timing of
postmalaria CD4 and viral

load

measurement.


In the preantiretroviral era, marked gains in life expectancy

for patients with AIDS were
achieved through aggressive OI management.
120
The same rigor that led to effective
guidelines for the control

of Pneumocystis jiroveci in developed countries must now be

brought to bear on the control of malaria and other important

opportunistic pathogens
endemic to sub-Saharan Africa.
34



(!ama Archleves 13 okL 2011)