18th Expert Committee on the Selection and Use of Essential Medicines

(21 to 25 March 2011)

NEW FORMULATION – Section 6 Anti-infective medicines (Adults)

6.2.2: Other antibacterials

WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION

1. Summary statement
Inclusion of the tablet formulation of sulfamethoxazole 800mg and trimethoprim 160mg
(cotrimoxazole 960mg) is proposed to reduce mortality and hospitilisations among adults
living with HIV/AIDS (ALHIV).

The principal reasons for requesting this inclusion are as follows:

1. Cotrimoxazole (Sulfamethoxazole 800mg and trimethoprim 160 mg) prophylaxis

therapy (CPT) prevents pneumocystis jirovecii pneumonia (PCP), cerebral toxoplasmosis,
bacterial pneumonia, diarrhoea, isospora belli, malaria, and other infections in ALHIV.
This has led to a significant mortality benefit in clinical trials in low and high income
countries.

2. WHO Guidelines recommend CPT as part of the standard package of care available
to ALHIV.

3. In most settings CPT is recommended indefinitely.

4. The effectiveness of CPT is compromised by lapses in adherence, resulting in

cotrimoxazole-resistant bacteria.

5. Adherence and effectiveness of CPT will be improved with wider availability of this
tablet.

2. Name of the focal point in WHO submitting or supporting the application

Reuben Granich, WHO/HTM/HIV/ATC

3. Name of the organization(s) consulted and/or supporting the application

Not applicable

4. International Nonproprietary Name (INN, generic name) of the medicine

sulfamethoxazole/trimethoprim

5. Formulation proposed for inclusion; including adult and paediatric (if

appropriate)
Combination tablet comprised of sulfamethoxazole 800 mg, and trimethoprim 160 mg
for adult patients.

 
 6. International availability - sources, if possible manufacturers
INN and dosage  Manufacturer and Country 
Sulfamethoxazole 
800mg +  WHO prequalified: Roche Pharmaceuticals, 
Trimethoprim  Switzerland 
160mg 
   Cipla Ltd., India 
   Instituto Quimioterapico, Peru 

7. Whether listing is requested as an individual medicine or as an example of a

therapeutic group
This strength is proposed for the ‘Other Antibiotics’ category (6.2.2)

8. Information supporting the public health relevance

8.1 Epidemiological information on disease burden
As of December 2008, 95% of the world’s 33.4 million people living with HIV/AIDS
(PLHIV) were in low and middle income countries (1). In 2008 there were 2.7 million
new HIV infections, two million AIDS-related deaths, and 5.5 million people needing
antiretroviral therapy (1) (2).

Before antiretroviral therapy and pneumocystis jirovecii pneumonia (PCP) prophylaxis were
given to PLHIV, PCP occurred in 70-80% of patients with AIDS (3). Among those with
significant immunosuppression, approximately 20-40% die. The majority of PCP cases
occur in patients who are unaware of their HIV infection or not receiving HIV care
regularly (4). For patients with advanced immunosuppression who were seropositive for
T. gondii and not receiving prophylaxis with drugs active against T. gondii, the 12 month
incidence of toxoplasmosis was 33% (4). In resource limited settings where exposures to
bacteria are different than industrialized settings, deaths due to malaria, isosporiasis,
mycobacterium tuberculosis, and bacterial pneumonia are common in HIV infected persons
(5,6). Indeed, current evidence shows that HIV infection increases the risk of malaria and
worsens malaria outcomes (7) while malaria infection increases viraemia in HIV-infected
individuals (8).

While antiretroviral therapy has reduced mortality due to HIV, additional simple, safe,
and effective interventions are needed to prevent malaria, bacterial infections, and
improve survival among HIV-infected persons.

8.2 Assessment of current use

The WHO does not collect statistics on the 33 million PLHIV who are also taking
cotrimoxazole. The majority of the 5 million people on ART are also eligible for
cotrimoxazole.

In 2008, the WHO sent out a survey on CPT and IPT policy and implementation to 69
countries with a high burden of TB-HIV (9). 41 countries responded to the survey,
representing 82% of the global HIV burden and 85% of the global HIV/TB burden.
93% of these countries had a national CPT policy, and 66% had nation wide

 
 implementation. 51% of responding countries had a national IPT policy, with 28%
indicating nation wide implementation.

8.3 Target population

Some country guidelines recommend cotrimoxazole in HIV-infected individuals
regardless of immune status while others restrict cotrimoxazole to persons with a CD4 ≤
350 cells/µL or ≤ 200 cells/µL.

9. Treatment details (dosage regimen, duration; reference to existing WHO and

other clinical guidelines; need for special diagnostic or treatment facilities and
skills)
The last revision of WHO guidelines on cotrimoxazole prophylaxis therapy (CPT, 800
mg of sulfamethoxazole and 160 mg of trimethoprim daily) were published in 2006.
These guidelines contain the following recommendations for adults (10):
• In countries with a high prevalence of HIV and limited health infrastructure, CPT
should be initiated in all patients, regardless of CD4 count or WHO clinical stage.
• For countries who initiate CPT based on WHO clinical stage, CPT should be
initiated in ALHIV stages 2-4.
• For countries who initiate CPT based on CD4 count, CPT should be initiated in
ALHIV with a CD4 ≤ 350 cells/µL.
• Continue cotrimoxazole prophylaxis among adults living with HIV indefinitely
o Duration of CPT is country specific, and is sometimes discontinued in the
event of a severe adverse event or immunological recovery due to ART.
o In Uganda, cotrimoxazole prophylaxis therapy is recommended for all
HIV positive adults and children for life, and is discontinued only in the
event of a severe adverse event (11).

10. Summary of comparative effectiveness in a variety of clinical settings:

10.1 Identification of clinical evidence
10.1.1 Search strategies
Pubmed Search "HIV Infections"[Majr] AND "Trimethoprim‐
Sulfamethoxazole Combination"[Majr]: 404 

By title: 39

By abstract: 11

By article: 3

The critical outcomes of interest were improving survival and decreasing hospitalisations.

The GRADE hierarchy considers randomised controlled trials the best source of
evidence. Therefore the three randomised controlled trials were used (12-14), while the
other eight identified observational studies were excluded. One Cochrane systematic
review was identified for CPT in adults with HIV (15). Study summaries and the
GRADE table for cotrimoxazole 960mg daily can be found in Annex 1. The data indicate
3

 
 that CPT decreases hospitilisations and prolongs life in adults living with HIV. It is also
well tolerated with only 3.9% of patients in the three randomised studies (16-19)
experiencing a cotrimoxazole-induced adverse event.

10.2 Summary of available estimates of comparative effectiveness

Unfortunately, our search did not yield studies comparing the effect of cotrimoxazole to
other antibiotics on survival in persons living with HIV in resource limited settings.

11. Summary of comparative evidence on safety:

11.1 Estimate of total patient exposure to date
There are no sources which indicate total exposure to cotrimoxazole.

11.2 Description of adverse effects/reactions

The most frequent adverse effects of cotrimoxazole are adverse GI effects (nausea,
vomiting, anorexia) and sensitivity skin reactions (e.g., rash, urticaria), each reportedly
occurring in about 3.5% of patients (20). The incidence and severity of these adverse
reactions are generally dose related, and adverse reactions may occasionally be obviated
by a reduction in dosage. Hypersensitivity and hematologic reactions are the most serious
adverse effects of cotrimoxazole, reportedly occurring in less than 0.5% of patients.

11.4 Identification of variation in safety due to health systems and patient factors
Cotrimoxazole has been used extensively worldwide. No clinically significant differences
in safety have been identified due to differences in health systems and patient factors.

11.5 Summary of comparative safety against comparators

Cotrimoxazole: When analysing the ‘adverse events’ outcome the CPT Cochrane review
found that there was no significant difference (N=1405, RR 1.28, 95% CI 0.47 – 3.51)
compared to placebo (15). In the GRADE table (Annex 1) treatment-limiting adverse
events were more likely in patients on CPT (RR 1.89, 1.31-2.72). Using an absolute
measure of effect indicates that 36 in 1000 patients would experience a treatment-limiting
adverse event due to cotrimoxazole.

12. Summary of available data on comparative cost and cost-effectiveness within the
pharmacological class or therapeutic group*:
12.1 Range of costs of the proposed medicine
Cotrimoxazole 960mg tablet
Unit
Source
Price/Day
IMRES
0.0196
(Netherlands)
IDA (Netherlands) 0.0216
JMS (Uganda) 0.0224
MEG (Netherlands) 0.0226
MEDS (Kenya) 0.0305
MISSION
0.0308
(Denmark)
The table above was modified from
http://erc.msh.org/dmpguide/pdf/DrugPriceGuide_2008_en.pdf. The listed sources (e.g.
IMRES) are pharmaceutical suppliers. Costs are priced in USD.

 
12.2 Comparative cost-effectiveness presented as range of cost per routine outcome (e.g.
cost per case, cost per cure, cost per month of treatment, cost per case prevented, cost
per clinical event prevented, or, if possible and relevant, cost per quality-adjusted life year
gained)
Health economists suggest that a life-saving intervention that costs between two to three times
the gross national product (GNP) per year-of-life saved represents a reasonable expenditure (21).
Yazdanpanah et al. reported that using CPT would cost USD 200 / life-year gained (22). This
analysis was performed in Cote d’Ivoire, where the per capita GDP is USD 1700, making this a
cost-effective intervention. Given the vast majority of African countries have a GDP above USD
200 this cost-effectiveness research can also be generalised to other countries.

13. Summary of regulatory status of the medicine (in country of origin, and preferably in
other countries as well)
sulfamethoxazole-trimethoprim is off-patent

14. Availability of pharmacopoeial standards (British Pharmacopoeia, International

Pharmacopoeia, United States Pharmacopoeia)
Sulfamethoxazole-trimethoprim is available in the United States Pharmacopoeia.

Sulfamethoxazole-trimethoprim is available in the International Pharmacopoeia.

15. Proposed (new/adapted) text for the WHO Model Formulary

*Note the AHFS Drug Information book was used as a reference for this section (32).

Description: Sulfamethoxazole and trimethoprim are synthetic folate-antagnoist antibiotics.

Spectrum of activity: Cotrimoxazole has good activity against gram positive and negative
organisms, including pneumocystis jerovicii, stenotrophomonas maltophilia, nocardia, S. pneumoniae (some
resistance), Staphylococcus aureus/epidermidis/pyogenes, Streptococcus viridians, E.coli, T. gondii, Proteus spp.,
enterobacter spp., Salmonella, Shigella, Klebsiella, Yersinia, and enteric gram negative rods.

Mechanism of action: Sulfamethoxazole interferes with bacterial folic acid synthesis and growth
via inhibition of dihydrofolic acid formation from para-aminobenzoic acid. Trimethoprim blocks
the production of tetrahydrofolic acid by inhibiting the enzyme dihydrofolate reductase.
Therefore, these two antibiotics work synergistically against many bacteria by inhibiting two
consecutive steps of bacteria growth.

Dosage forms: Tablet comprised of Sulfamethoxazole 800mg and Trimethoprim 160mg

Indications: Sulfamethoxazole-trimethoprim is used to reduce mortality, infections, and

hospitalizations in HIV-infected patients.

Pharmacokinetics/Pharmacodynamics: Time until peak concentration: 2 hours

(trimethoprim), 4 hours (sulfamethoxazole).

Distribution: Trimethoprim is approximately 44% and sulfamethoxazole is approximately 70%

bound to plasma proteins. The volume of distribution for trimethoprim is 100-120 L while that
of sulfamethoxazole is 12-18 L.

 
Half life: 11 hours (trimethoprim) and 10 hours (sulfamethoxazole). The half life of trimethoprim
increases with renal impairment.

Metabolism: Sulfamethoxazole: Biotransformed to inactive compound by N4-acetylation.

Excretion: 60% of free trimethoprim excreted in urine, 84.5% of sulfamethoxazole excreted in

urine.

Contraindications: Sulfamethoxazole and trimethoprim are contraindicated in patients with

known hypersensitivity to any of these active ingredients

Precautions:
• Caution should be exercised when giving cotrimoxazole to patients with G6PD
deficiency.
• Gastrointestinal distolerance, rash (which can progress to Stephens-Johnson syndrome),
thrombocytopenia, leucopenia, hepatitis, and hyperkalemia can occur with administration
of cotrimoxazole.

Toxicity:
The most frequent adverse effects of cotrimoxazole are adverse GI effects (nausea, vomiting,
anorexia) and sensitivity skin reactions (e.g., rash, urticaria), each reportedly occurring in about
3.5% of patients (25). The incidence and severity of these adverse reactions are generally dose
related, and adverse reactions may occasionally be obviated by a reduction in dosage.
Hypersensitivity and hematologic reactions are the most serious adverse effects of cotrimoxazole,
reportedly occurring in less than 0.5% of patients.

Pregnancy: Although there are no adequate and controlled studies to date in humans, studies in
pregnant women suggest that the incidence of congenital abnormalities in those who received
cotrimoxazole was similar to that in those who received a placebo; there were no abnormalities in
10 children whose mothers had received the drug during the first trimester. In one report, there
were no congenital abnormalities in 35 children whose mothers had received cotrimoxazole at
the time of conception or shortly thereafter. Reproduction studies in rats using oral trimethoprim
(as cotrimoxazole) dosages up to 70 mg/kg daily have not revealed evidence of impaired fertility.

Drug Interactions
Megoblastic anemia has been reported in patients receiving cotrimoxazole and pyrimethamine
dosages exceeding 25mg weekly. Cotrimoxazole may decrease the efficacy of tricyclic
antidepressants.

Sulfonamides increase the effect of oral hypogylcemic agents, so close monitoring of these
patients is suggested. Cotrimoxazole also inhibits the metabolism of phenytoin. Administration
of cotrimoxazole and phenytoin may increase the half life by as much as 39% and decrease the
metabolic clearance by as much as 27%.

Sulfonadmides may also displace methotrexate from plasma protein binding sites, resulting in
increased free methotrexate concentrations. Nephrotoxicity has been reported in renal transport
recipients who were receiving cotrimoxazole and cyclosporine.

Administration of cotrimoxazole and digoxin may also result in increased digoxin levels, which
has been reported in geriatric patients.
6

 
Annex 1: Summary of selected studies for cotrimoxazole
Author Methods/design Population
Randomised, double-
blind placebo
controlled trial.
Blocked
randomisation (in
blocks of four) by
independent 545 HIV infected persons
statistician to assign aged 18 years and over not
eligible patients to on ART in Abidjan, Cote
Anglaret 99
one of the study d'Ivoire at the community
(Cote d'Ivoire)
regimens. clinic of Yopougon-Attie.
Sequentially 271 given intervention 270
numbered sealed given placebo.
packages containing
the treatment
assigned were
prepared by an
independent
pharmacy.
Between October, 1995, and
April, 1998, were enrolled
771 HIV-1 and HIV-1 &
Patients were randomly
HIV-2 dually seroreactive
assigned one daily tablet of
patients who had sputum-
Wiktor 1999 Randomised double CTX (n=386) or placebo criteria: HIV-2-seropositive
smear-positive pulmonary
(Ivory Coast) blind case-control (n=385) 1 month after the
TB (median age 32 years
start of a standard 6-month
[range 18–64], attending
Abidjan’s four largest
outpatient TB treatment
centres.
Two groups of HAART
naive adults with HIV
infection: patients newly
diagnosed as having TB and
receiving TB treatment
either for the 1st time or for
retreatment after relapse;
previously treated patients
not receiving treatment.
Lusaka, Zambia, the
University Teaching
Double blind placebo
Hospital (UTH) chest clinic.
Nunn 2008 controlled
1003 patients were
(Zambia) randomised clinical
randomised: 835 (416 CTX,
trial.
419 placebo) received TB
treatment, 762 (376 CTX,
386 placebo) of them newly
diagnosed previously
untreated patients and 73
(40 CTX, 33 placebo)
receiving a retreatment
regimen;168 (CTX 84
placebo) were not on
treatment but had received it
in the past.
Intervention Participants
Inclusion: HIV-1 or HIV-
1/HIV-2 with WHO stage 2
or 3 infection. Exclusion:
WHO stages 1 and 4,
current pregnancy or
Mean 9.6 months in CPT
CTX 960mg daily or breastfeeding, previous
arm, 9.5 months in placebo intervention compared to 124 in placebo. placebo HR placebo HR placebo HR
matching placebo history of sulfa intolerance,
Hgb < 7g/dL, PLT <
75*10^9/L, absolute
neutrophil count <
0.75*10^9/L, and
renal/hepatic failure
Inclusion criteria: All those
aged 18 years or older who
lived in Abidjan, who had
sputum-smear-positive
tuberculosis, and who were
HIV-1 seropositive or HIV-
1 and HIV-2 dually
seroreactive. Exclusion
patients because of low
mortality risk, pregnant
TB regimen. women,patients with
previously treated
tuberculosis, those allergic
to CTX, and those receiving
CTX prophylaxis for
prevention of a recurrence
of toxoplasmosis.
Inclusion criteria: newly
diagnosed, previously
untreated patients with
smear positive pulmonary
tuberculosis receiving TB
treatment (after 1 year,
patients receiving a
Randomised participants in retreatment regimen were
a 1:1 ratio to receive a also eligible) and clinically
supply of pre-labelled trial healthy people previously
drug 1) CTX or 2) matching treated for TB but no longer
placebo; (2 tablets to be receiving any
taken daily). Each CTX (400 treatment.WHO stage 4
mg sulfamethoxazole and 80 HIV diseases that were
mg trimethoprim). unlikely to survive more
than 2 weeks as well as those
with a history of
sulphonamide allergy and
those who needed treatment
with or were already
receiving CTX for other
indications.
Bacterial
Number of deaths and hospitilisations Isosporiasi
Follow-up Malaria Pneumoni Adverse events Losses to follow up Notes
avoided s
a
There were three
treatment limiting
Severe event: death or hospital admission. adverse events that
120 severe events in intervention group were related to
198 in placebo group. 84 participants 2 on CPT, 2 on CPT, 3 on CPT, cotrimoxazole, as More patients lost to follow
experienced at least one event with 20 on 11 on 26 on judged by the event up in the placebo group
documentation than in the CPT group.
arm Probability of remaining free of severe 0.07 (0.01, 0.19 (0.04, 0.16 (0.04, committee. Two Although the difference was
events after twelve months was 63.7% (of 0.56) 0.86) 0.73) episodes of grade 2 not statistically significant
95 on CPT) vs. 45.8% (of 98 on placebo) morbilliform rashes
(HR 0.57, 95% CI 0.43-0.75) and one episode of
grade 3 hepatitis for
CPT arm.
51 patients in the CTX group (13·8/100
person-years) and 86 in the placebo group
On April 1998, based on a
(25·4/100 person-years) died (decrease In
Study drug was review of the available
risk 46% [95% CI 23–62], p<0·001). 29
temporarily results, and since it was
patients on CTX (8·2/100 person-yr) and
discontinued for 68 984 patients were invited to thought no longer ethical to
47 on placebo (15·0/100 person-yr) were
patients (30 [7·8%] participate. Of these, 771 continue to enrol new
admitted to hospital at least once after
co-trimoxazole (78·4%) were enrolled.The patients, DSMB
randomisation (decrease 43% [10–64]),
group, 38 [9·9%] main reasons fornon- recommended suspension of
p=0·02). The rate of admissions for all
Not Not Not placebo group) and enrolment were not enrolment: ALL study
24 months diseases that could potentially have been
analysed analysed analysed permanently returning to the TB clinic patients received open-label
prevented by CTX (septicaemia, enteritis,
discontinued for ten (74%), transfer by the TB- CTXAntibiotic sensitivity
chest infection, urinary-tract infection, and
(2·7%) patients in the clinic physicians to a non- testing revealed that six
toxoplasmosis) was significantly lower for
co-trimoxazole group study clinic (22%), or death (86%) of seven isolates of
patients in the CTX group (2·7/100
and ten before enrolment (4%). non-typhoid salmonella
person-yr) than in the placebo group
(2·7%) in the placebo were sensitive to
(8·7/100 person-yr; HR 0·3 [0·2–0·7],
group. CTX.Median CD4-cell
p=0·001).There were significantly fewer
count 317cells/L)
admissions for septicaemia and enteritis in
the ctx group than in the placebo Group.
A total of 310 (147 CTX 163 placebo)
participants died, corresponding to death
rates of 27.3 and 34.4 per 100 person-yr.In Suspected adverse
the Cox regression analysis, the HR for events leading to a
death (ctx:placebo) was 0.79 (95% planned interruption
confidence interval 0.63 to 0.99). Ctx was of trial drug occurred
associated with a 21% reduction in all in 18 patients (12
Total of 1012.6 person-yr of
cause mortality. The effect of CTX waned CTX, 6 placebo); all
follow-up. Follow-up from
with time, possibly owing to falling except 6 (all CTX)
the time of randomisation No information on 78 (37
adherence levels; in a per protocol analysis resumed the trial
ranged from 0 to 46 months. Not Not Not CTX, 41 placebo) (9.3%) Patients previously treated
based on patients who spent at least 90% drug. The reactions
Every four weeks up to 16 analysed analysed analysed participants after for TB should be excluded.
of their time at risk supplied with study leading to permanent
weeks and every 8 weeks randomisation.
drug, the HR was 0.65 (0.45 to 0.93).The discontinuation were
thereafter until the close of
NNT to prevent one death was 141.8 Stevens Johnson sdr
the trial.
(95% CI 71.7 to 588.7).Analysis by CD4 and anaemia, itchy
count on the subset of participants with rash, swollen face
data available showed no evidence of and lips, peripheral
difference in benefit according to the level neuropathy, and two
of immunosuppression (P>0.5, test for cases of anaemia.
heterogeneity); no difference in benefit by
age or sex.
GRADE review for cotrimoxazole
Author(s): Amitabh Suthar Date: 2010-07-26
Question: Should 960mg of cotrimoxazole be used in HIV-infected persons?
Settings: Resource-limited
Bibliography: Anglaret et al. 1999 (14), Wiktor et al. (12), Nunn et al. (13)

 
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