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Safety and Efficacy of Co-Trimoxazole for Treatment and
Prevention of
Plasmodium falciparum
Malaria: A
Systematic Review
Christine Manyando
1
*, Eric M. Njunju
5
, Umberto D’Alessandro
2,3
, Jean-Pierre Van geertruyden
4
1 Department of Public Health, Tropical Diseases Research Centre, Ndola, Zambia, 2 Department of Public Health, Institute of Tropical Medicine, Antwerp, Belgium,
3 Medical Research Council Unit, Fajara, The Gambia, 4 International Health, University of Antwerp, Belgium, 5 Department of Biomedical Sciences, Tropical Diseases
Research Centre, Ndola, Zambia
Abstract
Introduction:
Cotrimoxazole (CTX) has been used for half a century. It is inexpensive hence the reason for its almost
universal availability and wide clinical spectrum of use. In the last decade, CTX was used for prophylaxis of opportunistic
infections in HIV infected people. It also had an impact on the malaria risk in this specific group.
Objective:
We performed a systematic review to explore the efficacy and safety of CTX used for P.falciparum malaria
treatment and prophylaxis.
Result:
CTX is safe and efficacious against malaria. Up to 75% of the safety concerns relate to skin reactions and this
increases in HIV/AIDs patients. In different study areas, in HIV negative individuals, CTX used as malaria treatment cleared
56%–97% of the malaria infections, reduced fever and improved anaemia. CTX prophylaxis reduces the incidence of clinical
malaria in HIV-1 infected individuals from 46%–97%. In HIV negative non pregnant participants, CTX prophylaxis had 39.5%–
99.5% protective efficacy against clinical malaria. The lowest figures were observed in zones of high sulfadoxine-
pyrimethamine resistance. There were no data reported on CTX prophylaxis in HIV negative pregnant women.
Conclusion:
CTX is safe and still efficacious for the treatment of P.falciparum malaria in non-pregnant adults and children
irrespective of HIV status and antifolate resistance profiles. There is need to explore its effect in pregnant women,
irrespective of HIV status. CTX prophylaxis in HIV infected individuals protects against malaria and CTX may have a role for
malaria prophylaxis in specific HIV negative target groups.
Citation: Manyando C, Njunju EM, D’Alessandro U, Van geertruyden J-P (2013) Safety and Efficacy of Co-Trimoxazole for Treatment and Prevention of
Plasmodium falciparum Malaria: A Systematic Review. PLoS ONE 8(2): e56916. doi:10.1371/journal.pone.0056916
Editor: Philip Bejon, Kenya Medical Research Institute (KEMRI), Kenya
Received November 10, 2012; Accepted January 15, 2013; Published February 22, 2013
Copyright: ß 2013 Manyando et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: Belgian Development Co-operation funded the process through an institutional collaboration between the Tropical Disease Research Center, Ndola,
Zambia, and the Institute of Tropical Medicine, Antwerp, Belgium. The funders had no role in study design, data collection and analysis, decision to publish, or
preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: cmanyando@yahoo.com
Introduction
Worldwide, malaria is one of the most important causes of
morbidity and mortality, with children under five years of age and
pregnant women being the most severely affected groups. [1] An
estimated 3?3 billion people were at risk of malaria in 2010. [2] Of
all geographical regions, populations living in sub-Saharan Africa
(SSA) have the highest risk of acquiring malaria; in 2010, 81% and
91% of malaria cases and deaths occurred in the World Health
Organisation (WHO) African Region [1].
Artemisinin-based combination therapy (ACT) is currently the
mainstay of malaria treatment in both children and adults, while
in pregnancy it can be used only in the second and third trimester.
[3] Pregnant women are more susceptible to malaria infection
than other adults, resulting in placental malaria and anaemia and
increasing the risk of low birth weight and infant mortality. [4–8]
Approximately 50 million women living in malaria-endemic areas
become pregnant each year, half of them in areas of SSA with
stable malaria transmission. The strategies to control malaria
during pregnancy rely on case management as well as on a
package of preventive measures including insecticide treated nets
(ITNs) and intermittent preventive treatment (IPTp) with
sulfadoxine-pyrimethamine (SP), a folate inhibitor [9] and as per
recommendation of WHO [10]. Malaria prevention is also
important for children because of their increased susceptibility to
severe illness and death. WHO recommends IPT with SP in
infants (IPTi) within the context of the expanded programme of
immunisation (EPI) as well as seasonal malaria chemoprevention,
previously known as IPT in children (IPTc), with amodiaquine
and SP given at regular intervals. This is in addition to the overall
recommendations for malaria control that include ITNs, Insecti-
cide Residual Spraying (IRS) and access to prompt diagnosis and
treatment for malaria patients. SP is currently the only antima-
larial drug used for IPTi or IPTp. However, SP efficacy for
treatment of symptomatic malaria has declined over the years,
raising concerns about its longevity for IPT [11].
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HIV infection, through immune suppression, affects the
acquisition and persistence of immune response to malaria. [12]
In SSA, HIV infection may cause an average increase of 1?3% in
malaria prevalence and of 4?9% in malaria-related mortality [13].
Each year an extra three million clinical malaria cases and 65,000
malaria-related deaths can be attributed to HIV infection. [13]
Among HIV infected pregnant women malaria infection [4,14–
17] and clinical malaria [18,19] are more frequent with the latter
giving rise to higher parasite densities than those in HIV-
uninfected pregnant women. The proportion of placental malaria
cases attributable to HIV co-infection increases with the number
of pregnancies: 21?3% during the first pregnancy, 41?2% in
second pregnancy and 58?2% in third or more pregnancies [20]
Further, immunological data indicate that HIV impairs parity-
related specific immunity. [5] Cotrimoxazole (CTX) prophylaxis is
currently recommended by WHO to prevent opportunistic
infections in persons living with HIV/AIDS. [21] In HIV infected
children, who are even more vulnerable, daily CTX prophylaxis is
also recommended to prevent HIV-related opportunistic infections
[22–25].
CTX is a drug combination consisting of trimethoprim and
sulfamethoxazole. Trimethoprim (2,4-diamino-5-(3,4,5 tri-
methoxybenzyl pyrimidine)) belongs to a group of compounds
with antibacterial and antimalarial activity. It is an inhibitor of
dihydrofolate reductase and has been shown to act as a
sulfonamide potentiator. [26] The inhibitory action of the
combination on bacterial metabolism and in treating bacterial
diseases has been well documented. [26,27] Burroughs Well-
come and Company introduced trimethoprim and sulfameth-
oxazole (5-methyl-3-sulfanilamidoisoxazole) in the ratio 1:5. In
dealing with bacterial infections, the dosage producing satisfac-
tory treatment contained 320 mg of trimethoprim plus 1?6gof
sulfamethoxazole daily in divided doses for about seven days in
adults. [28] A 1:5 combination of trimethoprim (8 mg/kg
bodyweight) and sulfamethoxazole (40 mg/kg bodyweight) was
found to effectively treat malaria infections in semi-immune
Figure 1. Prisma Flow Chart.
doi:10.1371/journal.pone.0056916.g001
Cotrimoxazole Malaria Control
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Nigerian children aged 5–12 years. [29] It was also effective in
treating chloroquine-resistant P falciparum infections. [29] CTX
is not gametocytocidal and its sporontocidal activity is unknown.
Therefore, Wilkinson and colleagues suggested in 1973, to
supplement CTX treatment with an effective gametocytocidal or
sporontocidal drug in order to interrupt transmission. [30] More
recently, several studies have confirmed higher gametocyte
carriage after SP compared to other antimalarial drugs, with
peak gametocyte prevalence at around seven days post-
treatment. [31–35] However, gametocytes present in the
peripheral blood after SP treatment seem to have low infectivity
for Anopheles gambiae sensu stricto (ss) mosquitoes [36]. A similar
increase of gametocyte carriage after CTX treatment has been
observed. [37] CTX has similar mechanisms of action and
resistance patterns to SP and therefore, concerns were raised on
the potential impact of CTX resistance on SP efficacy,
preventing the implementation of CTX prophylaxis in SSA
[38,39].
CTX is well known as an antibacterial drug but less as an
antimalarial. Nevertheless, considering the reports on the impact
of CTX on malaria, both in HIV-infected and uninfected
individuals, we reviewed the available evidence on safety and
efficacy of CTX as an antimalarial for both preventive and
curative use.
Methods
Study Selection
This systematic review follows PRISMA guidelines. We
included all electronically available, peer reviewed articles. We
included studies in English as well as abstracts for which a full
study was not available such as conference deliberations as long as
sufficient data for inclusion were provided. All eligible studies
irrespective of sample size were included (see attached flow chart).
A protocol for systematic reviews was not used to for this particular
review.
Study Participants
The studies included comprise sample populations who were
administered CTX for treatment or prophylaxis or any other
drug administered to compare efficacy and safety with that of
CTX. The review also includes data from in-vitro studies that
involve CTX. The patients involved include children, adults
and pregnant women, HIV/AIDs infected and uninfected
individuals.
Search Methods
A literature search was performed to identify publications
reporting on safety and efficacy of Cotrimoxazole for malaria
treatment or prophylaxis. The search terms included: ‘‘Cotri-
moxazole prophylaxis and malaria’’, ‘‘Cotrimoxazole malaria
treatment’’, ‘‘Cotrimoxazole malaria and HIV’’, ‘‘Cotrimoxazole
malaria drug resistance’’, ‘‘Cotrimoxazole, malaria in pregnan-
cy’’, ‘‘trimethoprim-sulfamethoxazole and malaria prophylaxis’’,
‘‘trimethoprim-sulfamethoxazole and sulfadoxine–pyrimeth-
amine’’. The search covered the period from 1962 to June
2012. The PubMed was last accessed on June 8
th
, 2012. The
same terms were used to search other databases such as the
ClinicalTrials.gov and the WHO International Clinical trials
Registry Platform (ICTRP). The articles identified were
downloaded and reviewed. Studies included were prospective
and most of them were done in West Africa, East Africa and a
few in Southern Africa. Articles selected were stratified
according to the target group (children, non pregnant and
pregnant adults) and HIV infected population.
Results
Cotrimoxazole for Treatment of Malaria
Several clinical trials reported that CTX was efficacious against
P. falciparum malaria, both in children and adults and was generally
safe as no adverse effects were reported from the studies reviewed
(Table 1). In the 70 s and 80 s, CTX was reported to be as
effective as chloroquine for treatment of malaria. Parasite
clearance rates were similar but fever clearance rates were higher
in the chloroquine group due to its antipyretic properties. No
recrudescence was observed up to 60 days post-treatment. [30,40]
However, CTX had no gametocytocidal effect. [29] In Tanzania,
in the mid 90s, CTX cleared 97% of infections by day seven, while
chloroquine only cleared 19%. [41] In 1991 and 1998, both in
The Gambia and Uganda, CTX and SP were both effective in
reducing fever, clearing parasitaemia and improving anaemia in
children less than five years of age with uncomplicated malaria
[42], although in Uganda efficacy varied by geographical areas.
[43] In 1999, in a hyperendemic area in Southwest Nigeria, both
SP and CTX had similar efficacy; and the gametocyte prevalence
and parasite density were high for both SP and CTX, though for
the latter it was lower than for SP. [44] Later, from 2001 to 2005,
in Kenya, Malawi and Nigeria several studies demonstrated that
CTX was still efficacious (up to and above 90%) as antimalarial
treatment in areas of high endemicity. [37,44–46]. These results
reveal that CTX compares with standard treatment of SP for
example in the two Kenyan endemic areas of Oyugi in the West
and Tiwi in the coast in that their clinical and parasitological
failure rates were similar. The combined incidence of parasito-
logical failure over 14 days for the combined sites for CTX was
11% and SP was 16% (RR:0.72, p = 0.29). The 14 day clinical
failure rate for the combined sites for CTX was 3.3% and for SP
5.5% (RR:1.69, p = 0.13) [45]. In Malawi in 2001, in the outskirts
of Blantyre, an area of high malaria transmission, children were
treated for malaria and pneumonia (using Integrated Management
of Childhood Illness - IMCI) dual classification). Their clinical,
parasitological responses as well as gametocyte prevalence were
obtained. The results revealed a total of 78.2% of children
receiving CTX and 80.0% receiving SP plus Erythromycine
reached adequate clinical and parasitological responses (ACPRs)
(p = 0.19) [37]. In a hyper-endemic area of south-western Nigeria,
there was 11% treatment failure after 14 days of follow up of
uncomplicated P. falciparum malaria for CTX which was used for
treatment of malaria as was chloroquine, mefloquine, and SP.
Independent predictors of failure were age ,3 years (ad-
jOR = 0.10; p = 0.007) and body temperature $38uC 2 days after
the commencement of treatment (adjOR = 4.9; p = 0.03 [46].
Cotrimoxazole Malaria Prophylaxis in Non Pregnant HIV
Positive Population
Cotrimoxazole prophylaxis is a well established strategy to
prevent opportunistic infections in HIV-infected individuals [47–
49]. Starting Highly Active Anti-Retroviral Therapy (HAART)
should not be a reason for not starting or interrupting CTX
prophylaxis as this was demonstrated to be beneficial when
maintained for more than a year after HAART commencement.
[50]. The rationale is that patients with CD4 cell counts .200
cells/
mL are still at higher risk of opportunistic infections [51–55].
At present, the threshold of CD4 cell counts above which CTX is
not advantageous has not yet been identified. [55] However, in the
DART trial, carried out in a region where the efficacy of CTX
Cotrimoxazole Malaria Control
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Table 1. Summary of prospective studies assessing Cotrimoxazole used for malaria treatment.
Country
(author) Year* Study population Type of study Sample size Outcome: Efficacy/Safety Comments
Nigeria
(Fasan O
et al)[
29
]
1970
p
5–12 years, school
children with
asymptomatic
parasitaemia
RCT, single dose
administered to
all children as:
(8 mg T & 40 mg
SX);
(4 mg T &
20 mg SX); 15 mg
CQ/kg body wt
against a placebo.
FU up to
14 days
200 CTX in single dose is efficacious
(cleared 100% parasitaemia in
less than 72 hrs) against
asymptomatic malaria infection
and is safe (no adverse
reactions reported)
Thailand
(Wilkinson
et al)[
30
]
1972
p
Adults, UM with pre-
treatment
gametocytaemia
Non-randomized
trial, CTX treatment
administered 12
hourly for 7?5 days.
(FU duration not
mentioned)
12 CTX cleared 100% asexual P.
falciparum parasites (no adverse
effects reported)
No gametocytocidal effect
RSA
(Hansford
et al)[
40
]
1978 all ages except
pregnant
women, UM
RCT, CTX versus
CQ. FU on days 7,
12, 42 and 60
63 (19 on std
CTX, 23 on high
dose CTX, and
21 on CQ)
CTX cleared 100% parasitaemia
in less than
3 days; CTX high dose (4 tablets
twice daily)
for 2 days cleared 100%
parasitaemia in
2?5 days. Efficacy comparable
to chloroquine,
pyrexia responded slower for
CTX. But
no recrudescence in 60 days
(no
adverse effects reported)
CTX at either dosage
appeared to have no
effect on gametocytes (by
day 21 no gametocytes
were detected).
Gambia
(Daramola
et al)[
42
]
1991
p
2 groups were
studied; Group
(1). 7 months
to 23 months,
UM and
ARI; Group (2).
1to
5?7years,
asymptomatic
parasitaemia.
Non-randomized
trial, CTX std
treatment. FU on
days 3, 6 and 21.
Group (1) 10 &
Group (2) 65
0% parasitaemia on days 3, 6
and 21
except 1 patient who was positive
on day 3
but reduced parasitaemia and
negative on
Day 21. 3?3% asymptomatic subjects
were
positive but markedly reduced
parasites after
6 days. (no adverse effects
reported)
Occurrence of low level of
R1 resistance to CTX in a
rural area was a concern.
Tanzania
(Mutabingwa
et al)[
41
]
1996
p
,5 years, UM,
P.falciparum
monoinfection
RCT, CTX versus
CQ (25 mg
base/kg over 3
days); FU day s
14, 21 and 28.
61 CTX vs
63 CQ
CTX cleared 97% within 7 days
compared to CQ which cleared
19%. (no adverse effects reported)
MPCT was 4?3 days for
CTX and 5?3 d for CQ.
(MPCT was 2?6 d for CTX
in 1975 in same area and
2?7 d in 1991 in Malawi).
Study conducted in multi-
drug resistant P.
falciparum malaria area.
Uganda
(Kilian AHD
et al)[
43
]
1996 ,5 years, UM, P.
falciparum
monoinfection
Non-randomized trial
CTX, with follow-up
on days 3, 7 and 14
3 geographical
areas: A1:66;
A2:43 A3:50
Effectiveness of 40/8 mg/kg
CTX differed significantly
according to geographical area
by parasitological failure rates
(43?9%,
34?9% and 10?0% for areas A1.,
A2. And
A3. respectively). (no adverse
effects reported)
Therapeutic effectiveness
is relative to micro-
epidemiology resistance
Kenya
(Omar et al)
[
45
]
1998 ,5 years, UM, P.
falciparum
monoinfection
RCT: CTX vs SP
(one dose). FU on
days 0, 1, 2, 3,
and 4.
A1K. CTX 66 and
SP 76; A2K CTX
57 and SP 69
CTX and SP were both .90%
efficacious
with similar fever clearance
time (FCT),
Parasite clearance time (PCT)
and
haematological findings.(no
adverse
effects reported)
Holo-endemic malaria
areas in Kenya, CTX use
could help to prevent the
development of anti-folate
resistance strains.
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prophylaxis was most questioned, co-administering CTX with
HAART halved mortality within the 72-week follow up. The effect
in Uganda was sustained beyond 72 weeks, consistent with the
reports that CTX is an effective agent for malaria prophylaxis in
semi-immune adults [55].
CTX prophylaxis administered to non-pregnant, HIV-infected
patients living in an area of moderate, stable malaria transmission
reduced the risk of malaria infection (Table 2). In Uganda, 128
HIV-infected adults on HAART and CTX with sustained HIV
viral load of #400 copies/
mL for a period of 4 years had a low risk
of malaria infection. [56] In another Ugandan prospective cohort
study carried out on HIV infected adults living in a high malaria
transmission area, CTX was associated with a 76% lower malaria
incidence rate. CTX combined with HAART or with both
HAART and insecticide-treated bednets (ITNs), reduced malaria
incidence by 92% and 95%, respectively. [47] Also in Uganda, in
an area with a high level of anti-folate resistance, ITN use and
CTX prophylaxis in HIV infected children reduced malaria
incidence by 97%. [25] In another study, during a 6-month follow-
up period, patients on CTX prophylaxis and HAART developed
no clinical malaria as this finding was attributed to low parasite
densities, as parasite densities correlate positively to occurrence of
symptoms. [57] Other than long-term HAART, which restores
immunity, long term use of CTX prophylaxis is perceived to
contribute to the host’s response induced by HAART to achieve
the asymptomatic P. falciparum parasitaemia. [57] Even when rates
of antimicrobial resistance to CTX are high among diarrhoeal
pathogens and other bacteria, CTX use is still associated with
reduction in mortality and reductions in malaria, diarrhoea, clinic
visits and hospital admissions. [58] Apart from reducing HIV
morbidity and mortality, an additional advantage of CTX and
HAART is malaria prevention and the provision of ITNs reduces
the incidence of malaria even further [25].
HIV exposed children experience increased morbidity and
mortality in their first years of life compared with HIV uninfected
children born to uninfected mothers. [59] Also in HIV-infected
children, CTX prophylaxis and ITN use reduced malaria
incidence dramatically in a highly endemic and highly resistant
to antifolate drugs malaria setting. [25] It is important to note that
the use of ITNs alone is associated with a 43% reduction in the
incidence of malaria. [25,60,61] In Uganda, despite high rates of
antimicrobial resistance to CTX among diarrhoeal pathogens and
other bacteria, CTX prophylaxis was associated with 46%
reduction in mortality and lower rates of malaria, diarrhoea,
and hospital admissions. Adverse reactions were rare and affected
only ,2% per person-year and these were mainly muco-cutaneous
in nature which resolved with therapy withdrawal. Restarting
CTX prophylaxis in 89% of affected individuals, none had any
further adverse reactions. [62] The rates of morbidity and
mortality reduction in Uganda are similar to those found in other
studies in Africa. [63–67] In randomized trials done in Uganda
and Zimbabwe from 2003 to 2004, CTX prophylaxis significantly
reduced mortality and malaria incidence in a sustained manner.
[55] Further, another study in Uganda revealed that CTX
prophylaxis taken by HIV infected individuals was associated with
decreased morbidity and mortality among HIV negative family
members [68].
Cotrimoxazole Malaria Prophylaxis in Non Pregnant HIV
Negative Population
There are few studies on CTX prophylaxis in non-HIV
infected, and most are reporting secondary analyses of HIV
related studies (Table 3). In Mali, CTX had a 99?5% and 97%
protective efficacy against symptomatic and asymptomatic malaria
infections, respectively. This was observed in an area of low
antifolate resistance and selection for SP resistant strains did not
Table 1. Cont.
Country
(author) Year* Study population Type of study Sample size Outcome: Efficacy/Safety Comments
Nigeria
(Sowunmi
A, et al)[
46
]
1998 &
2003
,13 years UM,
P.falciparum
monoinfection,
.1000 asexual
forms/
ml, no
concomitant
illness
RCT; CTX vs SP
or CQ; FU on days
1–7 and 14
Only 101
exposed to
CTX reported
CTX had 89% efficacy by day 14.
Of the 11% failures, predictors
of failure were age
,3 years and body temperature
$38uC2
days after treatment
commencement.
(no adverse effects reported)
Assessed in hyper-
endemic area of south-
western Nigeria
Nigeria
(Sowunmi
et al)[
44
]
1999 6 months-12 years,
UM, P. falciparum
malaria, .2,000
asexual forms/
ml
RCT; CTX vs SP CTX = 53;
SP = 49
CTX was 89% and SP 88%
efficacious
after 14 days
Hyperendemic malaria
Malawi
(Hamel et al)
[
37
]
2001 6 months to 5
years,
UM and
pneumonia
with P. falciparum
mono-infection,
.2,000 asexual
forms/
ml
RCT with CTX vs
SP+E for 5 days;
FU 1–4 days and
days 7 and 14
CTX = 104;
SP+E = 101
ACPR: 87?2% in CTX; 80% in SP+E;
ACR CTX 96?1% and SP+E88%
(p = 0?03); (no adverse effects
reported)
The Blantyre District is an
area of high P. falciparum
malaria
* = Year of study
P
= Year of publication).
ACPR = Adequate Clinical and Parasitological Response, ACR = Adequate Clinical Response, ARI = Acute Respiratory Infection, A1. = Bundibugyo area, Uganda. A2. =
Kabarole east area, Uganda. A3. = Kaba role west area, Uganda. A1K = Tiwi, Kenya, A2K = Oyugis, Kenya. CTX = Cotrimoxazole, CTX standard treatment = (2 tablets twice
daily for 5 days), CQ = Chloroquine, E = Erythromycin, FU = Follow up, Kg = kilograms, mg = milligrams, MPCT = Mean Parasite Clearance Time, RCT = Randomized clinical
trial, SP = sulfadoxine-pyrimethamine, std = standard, SX = sulfamethoxazole, T = Trimethoprim, UM = uncomplicated malaria,/
ml = per microlitre, vs = versus.
doi:10.1371/journal.pone.0056916.t001
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seem to occur. CTX was generally safe, as only one patient in the
Mali cohort with previous history of Hepatitis A infection and
equivocal evidence of past or recent infection with Hepatitis B
virus developed acute hepatitis which resolved after withdrawal of
CTX. [69] From August 2007 to April 2008, in Tororo, Uganda,
an area of extremely high malaria transmission and antifolate
resistance, the protective efficacy of daily CTX prophylaxis against
malaria in children was 39%. Thus, CTX prophylaxis was
moderately protective against malaria in HIV exposed infants
when continued beyond the HIV exposure period despite the high
prevalence of Plasmodium genotypes associated with antifolate
resistance. In this particular study, no episodes of skin reactions,
Table 2. Cotrimoxazole for malaria prophylaxis in non pregnant HIV positive population.
Country
(author) Year* Study population Type of study Sample size Outcome: Efficacy/Safety Comments
Uganda
(Mermin
et al) [
68
]
2001 & 2002 HIV-1 infected clients and
their HIV negative family
members
Prospective
cohort study
879 HIV infected
participants and
2771 HIV negative
family members. HIV
infected participants
received daily CTX
and
household family
were
followed up to 17
months (+ initial 5
months of visits)
CTX prophylaxis taken by HIV
persons was associated with
decreased morbidity and
mortality among HIV negative
family members ,10 years.
Mortality reduced by 63% and
malaria was less common
(IRR = 0?62 p,0?0001)
Concerns
regarding the
spread of
bacterial
resistance should
not impede
implementation
of CTX programs
Uganda
(Mermin
et al)[
62
]
2001 to 2003 $5 years and ,5 years, on
CTX prophylaxis, FU for 1?5
years
Prospective
observational
cohort study
509 HIV-1 infected
and 1522
HIV-negative
household members
CTX reduced mortality by 46%
and lower rates of malaria
(incidence 0?28[0?19–0?40],
p,0.0001), diarrhoea
(0?65[0?53–0?81] p,0?0001)
and hospital admission
(0?69[0?48–0?98]. Rare
adverse reactions (,2%
per person-year)
CD4 annual
decline was less
and annual
increase in viral
load was lower.
Study conducted
in an area with
high rates of
antimicrobial
resistance to CTX
Uganda
(Mermin
et al)[
47
]
2001; 2001 to
2003; 2003 to
2004; 2004
to 2005
$18 years Prospective
cohort study
done in 4
phases
2001:466 (of whom
399 on CTX
prophylaxis);
2003:138 survivors
from first cohort plus
897
new participants on
ART & CTX, 2004:
the participants were
given ITNs
Baseline: 50 episodes/100
persons per year; CTX prophylaxis
only: 76% lower malaria, 9
episodes/100 persons per year;
ART+CTX: 92% lower malaria rate
(IRR 0?24 [0?15–0?38], p,0.0001;
ART, CTX and ITNs: 95% lower
malaria rate
(IRR 0?05 [0?03–0?08],
p,0.0001
Study areas are
high –intensi ty
transmission
areas.
Uganda &
Zimbabwe
(Walker
et al)[
55
]
2003 to 2004 Adults $18 years,
symptomatic AIDS stage
2–4, CD4 counts ,200/
mL,
no previous ART apart
from PMTCT commenced
on triple-drug ART.
Observational
study from DART
trial. CTX
prophylaxis was
not routinely
used but
variably
prescribed by
clinicians. FU was
from 4?5to
5?3 years.
3179 participants CTX prophylaxis reduced mortality
(odds ratio: 0?65; p = 0?001) up
to 12 weeks; sustained from
12–72 weeks
but not evident subsequently.
CTX prophylaxis reduced
frequency of malaria (odds ratio
0?74; p20?0005), maintained
with time.
CTX prophylaxis
for at least 72
weeks for all
adults starting
combination ART
is recommended
Uganda
(Nakanjako
zt al)[
56
]
2004 to 2005 33–44 years on HAART &
on CTX prophylaxis,
sustained HIV viral load,
,400 copies/ml for
4 years,
Prospective
observational
cohort
128 patients
systematically
selected
4% ha d asymptomati c HRP2
antigenaemia in PLHIV on
long term use of HAART
and CTX.
(no adverse effects reported)
Observation made
in low to
moderate stable
malaria
transmission area
Uganda
(Kamya
et al)
(24)
2005 to 2006 1–10 years vs 1–11 years
healthy children;
Prospective
cohort study:
CTX+ITNs in
HIV infected
children vs
ITNs in
Healthy children
300 HIV infected
children on CTX +
ITNs
& 561 healthy
children received
ITNs
CTX +ITNs: 97% reduction
in malaria incidence (P,0?001).
ITN use: 43% reduction in
malaria incidence (P,0?001)
Study conducted
in malaria
endemic area
with high level of
molecular markers
of antifolate
resistance
* = Year of study.
ART = Anti-Retroviral Therapy, CTX = Cotrimoxazole, DART = Development of Anti-Retroviral Therapy, HAART = Highly Active Anti-retroviral Therapy, HRP = histidine rich
protein, HIV = Human Immunodeficiency virus, IRR = Incidence rate ratio, ITNs = Insecticide Treated Nets, PLHIV = people living with HIV/AIDs, PMTCT = prevention of
mother to child HIV transmission.
doi:10.1371/journal.pone.0056916.t002
Cotrimoxazole Malaria Control
PLOS ONE | www.plosone.org 6 February 2013 | Volume 8 | Issue 2 | e56916
allergic drug reactions or other unexpected adverse reactions were
reported with CTX administration [70].
Cotrimoxazole Malaria Prophylaxis during Pregnancy
Numerous studies have demonstrated that HIV infection nearly
doubles the risk of placental malaria. [16,20,71] Some trials
suggest that monthly IPT-SP regimens in HIV infected pregnant
women can decrease the risk of placental malaria to levels seen
among HIV-uninfected women receiving 2-dose IPT. [72,73] In
HIV infected pregnant women on daily CTX, SP-IPT is not
indicated as it may be associated with overlapping toxicities. [74]
Fortunately, CTX prophylaxis has shown to decrease the
prevalence of placental malaria in HIV infected women as much
as IPT-SP in HIV uninfected women (Table 4).
A Malawian study observed a superior efficacy of CTX with or
without SP-IPT compared to SP-IPT alone in reducing prevalence
of microscopic and PCR-detected malaria infections and anaemia
in HIV-infected pregnant women. [75] When taken in the first
trimester, CTX intake in pregnancy has been associated with
increased risk of folate deficiency, maternal anaemia and poor
birth outcomes [76–79] and neural birth defects [80–82].
However, in the same Malawian study, CTX, with or without
SP-IPT, was associated with reduced prevalence of maternal
anaemia and higher haemoglobin concentration, consistent with
beneficial effects in birth outcomes as previously reported in a
Zambian study. [83] This further underscores the fact that for this
target group, CTX prophylaxis may be beneficial. Therefore,
Newman et al concluded that daily CTX can decrease the risk of
placental malaria in HIV infected women [84].
Table 3. Cotrimoxazole malaria prophylaxis in non pregnant HIV negative population.
Country
(Author) Year* Study population Type of study Sample size Outcome: Efficacy/Safety Comments
Mali
(Thera)[
69
]
2000 5–15 years in an on-going
cohort study of incidence
of malaria were eligible for
inclusion
RCT within Cohort study 160 in CTX group & 80
in the SP group
(control).
FU periods 11?8
weeks
in CTX group and 11?7
weeks in
SP group.
From baseline the
prophylactic efficacy
of CTX against
uncomplicated malaria was
99?5% (CI 95: 96%–100%;
p,?001) and 97% efficacy
against infection.
Seasonal malaria
transmission but
intense. Study
was conducted in
peak malaria
season
Uganda
(Sandison
et al)[
70
]
2007 to
2008
6 weeks –9 months,
documented HIV
uninfected
status with mother
HIV infected,
current breast feeding
Non-blinded RCT: CTX
prophylaxis from
enrolment until cessation
of breast feeding and
confirmation of negative
HIV status OR uninfected
children randomized to
stop CTX prophylaxis
immediately or continue
until 2 years old.
203 breastfeeding HIV
exposed infants; 185 HIV
negative randomized to
stop or continue until 2
years.
CTX when continued
beyond the period of
HIV exposure = 3.24
cases/person year; When CTX
was stopped = 5.57
cases/person year.
CTX yielded 39% reduction
in malaria incidence
(IRR 0?61 (95% CI 0?46 to
0?81), p = 0?001)
Area of study has
high prevalence
of plasmodium
genotypes
associated with
antifolate
resistance.
* = Year of study.
CTX = Cotrimoxazole, FU = Follow up, IRR = Incidence Rate Ratio, PLHIV = people living with HIV/AIDs, RCT = Randomized clinical trial, SP = sulfadoxine pyrimethamine.
doi:10.1371/journal.pone.0056916.t003
Table 4. Cotrimoxazole for malaria prophylaxis during pregnancy in HIV positive population.
Country
(Author) Year* Study population Type of study Sample size Outcome: Efficacy/Safety Comments
Malawi (Kapito-
Tembo)[
75
]
2005 to 2009 $15 years, Gestation $34 weeks
attending routine antenatal
services
Cross sectional study 1121 had data on
CTX and/or SP-IPT
intake
CTX+SP-IPT: microscopic
malaria 0 ?6%, PCR: 3?6%
CTX only: microscopic malaria
2?7%, PCR 5?5% SP only:
microscopic malaria 7?7%,
PCR 13?5%
Uganda
(Newman)[
84
]
2008 to 2009
(HIV infected)
2008 (HIV
un-infected)
23 to 33 years old PLHIV women
at delivery, 19 to 29 years old
HIV-uninfected women at
delivery
Cross sectional study
comparing placental
malaria prevalence
between HIV-infected
women prescribed
CTX and
HIV-uninfected
women prescribed
IPT SP
150 HIV-infected
women on
CTX; 336
HIV-uninfected
womenonSP-IPT
HIV+ CTX: 19% placental
malaria smear, PCR positive
6% HIV- SP-IPT: 26%
placental malaria, PCR
positive 9%
High malaria
transmission
area
* = Year of study (if not available P = Year of publication).
CTX = Cotrimoxazole, HIV = Human Immunode ficiency virus, PCR = Polymerase Chain Reaction, PLHIV = people living with HIV/AIDs, SP-IPT = sulfadoxine-
pyrimethamine-Intermittent Preventive Treatment.
doi:10.1371/journal.pone.0056916.t004
Cotrimoxazole Malaria Control
PLOS ONE | www.plosone.org 7 February 2013 | Volume 8 | Issue 2 | e56916
Most studies have demonstrated CTX not associated with
hyperbilirubinemia when administered to mothers during preg-
nancy and breast feeding. No cases of kernicterus were reported in
neonates after maternal ingestion of sulfonamides [74,85,86].
Further, the database on drugs and lactation revealed that
although CTX is detected in breast milk, exposure through breast
milk appears to be safe in healthy breastfed infants. [87] Further, a
manifestation of small for gestational age was mentioned in a
recent study of women exposed to CTX during second and third
trimesters compared to those exposed to other urinary antimicro-
bials and this was classified as uncommon in frequency [86,88].
There is currently no information on the use of CTX as malaria
prophylaxis in HIV-uninfected pregnant women.
CTX Resistance Versus SP Resistance in P. falciparum
The dihydrofolate reductase (dhfr)/dihydropteroate synthetase
(dhps) quintuple mutant is known to be associated with SP
treatment failure. It is however unclear whether the quintuple
mutant affects the protective efficacy of CTX against malaria.
[89–91] A study in Uganda carried out between 2008 and 2009
found a similar prevalence of placental malaria and resistance
markers (dhfr -59; dhps-437 or dhps-540E) in HIV-infected pregnant
women taking CTX and HIV–uninfected women taking SP-IPTp
[84].
Considering the possible cross resistance between CTX and SP,
[92,93] there have been concerns on the impact of widespread
CTX prophylaxis on the selection of SP resistant malaria parasites.
[38,39] Nevertheless, recent studies in Tororo and Kampala,
Uganda, found no association between CTX use and increased
prevalence of mutations conferring antifolate resistance in HIV
infected children and adults taking daily CTX prophylaxis [94,95]
(Table 5).
In Uganda, CTX prophylaxis in HIV-infected individuals did
not increase the occurrence of SP-resistant malaria episodes
Table 5. P. falciparum malaria – CTX resistance or CTX resistance versus SP resistance.
Country
(Author) Year* Study population Type of study Sample size Outcome: Efficacy/Safety Comments
Liberia
(Petersen
1987)[
98
]
1987 Plasmodium falciparum
isolates were tested against
sulfadoxine,
sulfamethoxazole,
pyrimethamine and
trimethoprim
In vitro
susceptibility
testing
Two isolates F32 (from
Tanzania and sensitive to
chloroquine and
pyrimethamine) & K1 (from
Thailand and resistant to
Chloroquine and
pyrimethamine)
The difference in IC
50
between
F32 and K1 against trimethoprim
and CTX was much less than the
difference between the IC
50
values against pyrimethamine
and SP.
Cross resistance
between
pyrimethamine
and
trimethoprim
exists but is not
complete.
Uganda
(Malamba
2010)[
95
]
2001 3 to 34?5 years HIV infected
adults and children
Prospective
cohort study
administering
CTX prophylaxis
3,601 blood smears
(2,154 taking taking CTX
prophylaxis and 1,447
not taking CTX
HIV infected taking CTX: dhfr
triple mutant: 74% dhps
mutant: 95% dhfr/dhps quintuple
mutant 6: 73% HIV infected not on
CTX dhfr triple mutant:
70%(P = 0?71) dhps mutant: 88%
(p = 0?21) dhfr/dhps quintuple
mutant: 64% (p = 0?36).
Extremely high
malaria
transmission
area.
Uganda
(Malamba
et al)[
96
]
2001 and
2002
$5 years and ,5 years, HIV
uninfected household
members of PLHIV taking or
not taking CTX.
Prospective
cohort study
1,319 HIV-uninfected
household members of
PLHIV taking CTX; 1,248
HIV uninfected
household members of
PLHIV not taking CTX.
Proportion of malaria episodes
caused by SP-resistant parasites;
HIV un-infected persons =
HIV-infected household members
not taking CTX. (Overall incidence
of malaria [IRR = 0?67, 95%
CI = 0?49–0?92])
No evidence
that CTX
prophylaxis lead
to the spread of
SP resistant
malaria parasites
among
household
members not
taking the drug.
Kenya (Hamel
et al)[
97
]
2002 to
2003
$15 years, not severely ill,
not taking daily antibiotics
for treatment of a chronic
illness (excluding
tuberculosis)
Prospective study
to assess whether
the use of daily
CTX resulted in
significant changes
in antifolate and
CTX resistance
among common
organisms
3 study arms: 132 HIV
negative 336 HIV-positive
with CD4$ 350/
mL received
daily vitamins 692 HIV-
positive with CD4,350
received daily CTX;
median FU 24
weeks
Daily CTX
did not result in increased
P.falciparum antifolate resistance;
reduced malaria incidence by
89–90%
Contributed to increased
pneumococcus and commensal
E. coli resistance (in lower
CD4 subjects P,0.005)
There is need for
surveillance with
regard to CTX
resistance
among
respiratory and
diarrhoeal
disease
pathogens
Uganda
(Gasasira
et al)[
94
]
2004 to
2005 &
2005 to
2006
HIV-infected children 1–10
years and healthy children
1–11 years;
2 prospective
cohort studies:
ITN +CTX and ITN
292 HIV-infected
children; Duration of FU: 0
to 2?4 years 517
uninfected children;
Duration of FU = 0?2to
2?4 years HIV
uninfected
CTX gave 80% protective efficacy
and this did not vary over 3
consecutive (9?5 month) periods;
Prevalence of dhfr 164L mutation
was higher in parasites from HIV
infected compared to HIV
uninfected children (8% vs 1%,
p=0?001)
Study
conducted in an
area of
widespread
antifolate
resistance.
* = Year of study.
CTX = Cotrimoxazole, DHFR = Dihydrofolate reductase, DHPS = Dihydropteroate synthetase, E. coli = Escherichia coli, FU = Follow up, HIV = Human Immunodeficiency
Virus, IRR = Incidence Rate Ratio, PLHIV = people living with HIV/AIDs, RCT = Randomized clinical trial, SP = sulfadoxine pyrimethamine.
doi:10.1371/journal.pone.0056916.t005
Cotrimoxazole Malaria Control
PLOS ONE | www.plosone.org 8 February 2013 | Volume 8 | Issue 2 | e56916
among HIV-uninfected individuals living in the same household.
Instead, the latter had a lower incidence of malaria and infections
with SP resistant parasites. [96] In Kenya, a prospective study
observed that daily CTX increased carriage rates of
non-susceptible pneumococci and CTX resistant E.coli and
therefore may accelerate the development of CTX resistance
among respiratory and diarrhoeal pathogens, especially in areas
with low CTX resistance at baseline. [97] However, regarding
malaria, this study demonstrated that CTX prophylaxis reduced
the incidence of malaria and antifolate resistant genotypes.
In-vitro susceptibility testing against sulfadoxine, sulfamethoxa-
zole, pyrimethamine and trimethoprim on P. falciparum isolates
from Tanzania and from Thailand revealed incomplete cross-
resistance between pyrimethamine and trimethoprim. The cross
resistance between CTX and SP did not appear to be absolute at
the time of testing [98].
CTX Resistance of Pathogens Other than Plasmodium
Cotrimoxazole is often used to treat pneumoccal infections.
There were concerns related to the use of CTX and SP regarding
increased resistance in pathogens other than pneumococci, such as
Haemophilus influenzae and dysentery-causing bacteria. [99] How-
ever, a study done in Uganda reported by Mermin (2005) revealed
that daily CTX prophylaxis, taken by persons with HIV, was
associated with decreased morbidity and mortality among family
members. Antimicrobial resistance among diarrhoeal pathogens
infecting family members did not increase. Concerns regarding the
spread of bacterial resistance should therefore not impede
implementation of CTX program [68].
Discussion
Artemisinin Combination Therapies (ACTs) are very efficacious
and are currently the mainstay for malaria treatment. However,
for prophylaxis the options are limited. Despite the high and
increasing drug resistance, only SP is at present eligible to be used
for IPTp and IPTi. [100] It is unclear what could be a valid
alternative to SP as newer drugs are still in the pipeline of
development to be used for IPTp such as Mefloquine, Dihy-
droartemisinin-piperaquine, chloroquine-azithromycin and SP-
azythromycin. This review indicates that CTX may be a possible
alternative as there is a long history of CTX remaining efficacious
and safe for malaria treatment and prophylaxis for different target
groups.
The wealth of information available on the use of CTX in HIV
infected people confirms that CTX is effective against malaria
infection and in preventing clinical malaria. Further, despite its
long term use, CTX is not associated with a higher prevalence of
mutations related to antifolate resistance and works synergistically
with ITNs in preventing malaria. Therefore, CTX can be
successfully used to prevent HIV/AIDS-related opportunistic
infections and malaria morbidity, an important feature in sub-
Saharan Africa where these two diseases co-exist and health
services operate under constrained budgets. Besides being
relatively safe CTX is also inexpensive, almost universally
available and has a wide clinical spectrum of activity spanning
from bacteria, fungi and protozoan infections [101].
The safety concerns for CTX is related to its impact in
malnourished individuals in whom it may precipitate folate
deficiency and pancytopaenia. [102] Common gastrointestinal
disturbances include nausea and vomiting and less commonly
diarrhoea. Cholestatic jaundice had also been documented.
Sulfamethoxazole is known to cause headache, depression and
hallucinations. [102] Hypersensitivity reactions like neutropenia,
Stevens-Johnson syndrome (SJS) and Sweet’s syndrome occur
more often in HIV/AIDs patients. [102] The reactions in this
group have been related to their poor ability to handle nitroso-
derivatives of sulfamethoxazole. [103,104] Generally, the wide use
over time has proven CTX to be safe.
The fact that in pregnant women CTX prophylaxis showed a
similar prevalence of placental malaria in HIV infected women as
IPT-SP in HIV uninfected women suggests that daily CTX can
similarly decrease the risk of placental malaria. In HIV-infected
pregnant women, CTX use was associated with decreased malaria
infection, maternal anaemia and increased haemoglobin concen-
tration, a finding consistent with the beneficial effects on birth
outcomes. Therefore, CTX may have similar beneficial effects in
other groups though there is currently no data available on its use
as a malaria preventive measure in HIV uninfected pregnant
women or children. The studies reporting on CTX prophylaxis in
HIV infected pregnant women were cross-sectional studies and
there could be residual confounding from unmeasured factors.
Further, participants were only enrolled in the third trimester of
pregnancy [75] and at delivery [84] and therefore the overall
impact of CTX on malaria infection and anaemia may be
underestimated. Despite these limitations, these studies provide
important data on the impact of CTX prophylaxis on the
epidemiology and clinical implications of placental malaria among
HIV-infected women.
A limitation of this review is that most information available
comes from East and Western Africa. Almost all cited publications
are published in English and relevant literature in other languages
may have been overlooked. Nevertheless, this review identified the
need of determining the benefits of using CTX in HIV-uninfected
risk groups, such as children and pregnant women. The
constraints related to the use of CTX may relate to the fact that
it should be taken daily and issues related to its acceptability,
safety, adherence and potential selection of resistant strains
including antibiotic resistance.
Conclusions
CTX has been extensively used for half a century as an
antibiotic worldwide and in malaria endemic areas. CTX
antimalarial effect, although scientifically proven, has been
ignored. Its long term use in HIV infected children and adults,
has proved that CTX is still effective for malaria prevention and
treatment. This has been confirmed in a few studies in non-HIV
infected population, mostly secondary analyses of HIV studies.
More information is required for pregnant women, irrespective of
HIV infection for whom no information is available. There is need
for more randomized controlled trials to evaluate further the
efficacy of CTX as antimalarial, since most of the available data
are derived from descriptive studies.
Research on CTX safety, adherence and acceptability is still
necessary if its role for malaria treatment and prophylaxis in
groups other than HIV-infected individuals is to be established.
Author Contributions
Conceived and designed the experiments: CM JPV. Performed the
experiments: CM JPV. Analyzed the data: CM EN UDA JPV. Wrote the
paper: CM EN UDA JPV.
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