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Int J STD AIDS OnlineFirst, published on November 18, 2014 as doi:10.1177/0956462414560594

Original research article

International Journal of STD & AIDS
0(0) 1–6
! The Author(s) 2014
Alternative treatment approach to Reprints and permissions:
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cerebral toxoplasmosis in HIV/AIDS: DOI: 10.1177/0956462414560594
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experience from a resource poor setting

Rama Prosad Goswami1, Rudra Prosad Goswami2,

Mehebubar Rahman1, Yogiraj Ray1 and
Santanu Kumar Tripathi3

Abstract
The current standard treatment for cerebral toxoplasmosis (pyrimethamine/sulfadiazine) often encounters problems of
poor tolerability, adverse effects, frequent dropouts and non-availability of pyrimethamine/sulfadiazine in some parts of
India. We had to use the combination of two effective alternative agents for toxoplasmosis, cotrimoxazole and clinda-
mycin, on compassionate ground. This retrospective observational study reports superior efficacy and better tolerability
of cotrimoxazole/clindamycin compared to recommended regimen. Primary end-point (complete response) was defined
as more than 50% improvement of clinical status or more than 50% decrease in the size of brain lesions after two weeks
of treatment initiation. Complete response occurred more commonly in cotrimoxazole/clindamycin than in pyrimeth-
amine/sulfadiazine (80% vs. 31.25%, respectively, relative risk 2.56, 95% confidence interval: 1.21–5.43). There was a
trend towards higher on-treatment mortality in pyrimethamine/sulfadiazine in comparison to cotrimoxazole/clindamycin
group (mortality rates 37.5% in pyrimethamine/sulfadiazine vs 12% in cotrimoxazole/clindamycin, p ¼ 0.07, relative
risk ¼ 3.125, 95% confidence interval: 0.91–10.75). Overall, 62.5% (10/16) patients in pyrimethamine/sulfadiazine suffered
drug-related adverse reactions compared to 24% (6/25) in cotrimoxazole/clindamycin (p ¼ 0.02, relative risk ¼ 2.60, 95%
confidence interval: 1.17–5.76). Commonest complication in pyrimethamine/sulfadiazine was severe thrombocytopenia
with major bleeding (4/16, 25%). We propose that the new combination chemotherapy, which is widely available,
effective and safe, can be practiced in developing countries.

Keywords
Cerebral toxoplasmosis, HIV/AIDS, clindamycin, cotrimoxazole, combination therapy, India, resource poor setting

Date received: 1 August 2014; accepted: 26 October 2014

on compassionate ground as the PYR was only irregu-

Introduction larly available in West Bengal, India, either in commer-
Cerebral toxoplasmosis is the most common opportun- cial market or from Government sources. It is
istic infection of the central nervous system in people worthwhile to mention that a lot of third-world
living with HIV/AIDS.1 The current recommended
treatment consists of the combination chemotherapy 1
Department of Tropical Medicine, School of Tropical Medicine, Kolkata,
with pyrimethamine (PYR) and sulfadiazine (SULF).2
India
The most significant problem of this combination 2
Department of Rheumatology, Institute of Post Graduate Medical
chemotherapy is poor tolerability, high rates of adverse Education and Research, Kolkata, India
3
effects and drop outs. Cotrimoxazole (CTX) has been Department of Clinical and Experimental Pharmacology, School of
shown to be an acceptable alternative with comparable Tropical Medicine, Kolkata, West Bengal, India
efficacy as has been PYR-clindamycin (CLD) combin-
Corresponding author:
ation therapy.3 Rudra Prosad Goswami, Abhyudoy Housing, Flat, 18/14, ECTP, Ph IV,
We started to use the combination of the two effect- Type B, EM Bypass, Kolkata, 700107, West Bengal, India.
ive alternative drugs for toxoplasmosis, CTX and CLD, Email: rudra.goswami@gmail.com

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2 International Journal of STD & AIDS 0(0)

countries use trimethoprim (TMP)/sulphamethoxazole As described in a previous study, response was

(SMX) for cerebral toxoplasmosis because SULF is far defined clinically and by CT scan. Primary end point
too expensive and SULF availability is also irregular in (complete response) was defined as more than 50%
certain global regions like Italy (unpublished data). We improvement of clinical status or more than 50%
report in this retrospective observational study the decrease in the size of brain lesions after two weeks of
superior efficacy and better tolerability of TMP-SMX- treatment initiation. Partial response was defined as less
CLD combination chemotherapy for the treatment of than 50% improvement of clinical status and less than
cerebral toxoplasmosis. 50% decrease in the size of brain lesions after two
weeks of treatment initiation. Treatment failure is
defined as no improvement either clinical or radio-
Materials and methods logical; deterioration except within first three days;
We retrospectively reviewed the hospital records of death; major toxicity amounting to treatment
AIDS patients with a first episode of cerebral toxoplas- withdrawal.5
mosis who were admitted under our care at the School Proportions were expressed as percentages and
of Tropical Medicine and Institute of Post Graduate ratios. Continuous data were expressed as mean 
Medical Education and Research, Kolkata, India, in standard deviation. Categorical variables were com-
the past 4 years (January 2009 to January 2013). The pared using the Chi square test or Fischer’s exact test
investigators’ clinical records of patients managed under when Chi square test was not applicable. Continuous
their care at inpatient and outpatient departments were variables were compared with Students t test. All stat-
analysed anonymously with permission from the appro- istical analyses were performed using SPSS version 16.0
priate authorities. Waiver of approval was granted by (SPSS Inc., Chicago, IL).
the Clinical Research Ethics Committee, Calcutta
School of Tropical Medicine, Kolkata.
Cerebral Toxoplasmosis was diagnosed in 41 HIV-
Results
seropositive patients in this study with three parameters Forty-one HIV patients with diagnosis of cerebral
toxoplasmosis were admitted. Average age of the popu-
(i) Clinical symptoms (fever, headache, focal neuro- lation was 32  8.6 years (interquartile range
logic deficits), [IQR]: 13). Thirty-three (80.48%) of them were men.
(ii) Computed tomography (CT), MRI findings (ring One of them was on HAART (second line regimen
enhancing lesions), with tenofovir, lamivudine and atazanavir/ritonavir).
(iii) Positive toxoplasma IgG antibody. Others were HAART naive. Average CD4 count was
82.46  17.15/mL. Details of the baseline characteristics,
Patients were treated with combination chemother- clinical symptomatology, co-morbidities and treatment
apy consisting of either pyrimethamine with sulfadia- responses are given in Table 1.
zine (PYR-SULF) or cotrimoxazole and clindamycin Sixteen patients received recommended first-line
(CTX-CLD). Informed consent was taken for all combination chemotherapy consisting of PYR-SULF.
patients before starting CTX-CLD. Twenty-five patients received combination therapy con-
PYR-SULF consisted of PYR 200 mg on 1st day sisting of CTX-CLD. Cerebral oedema whenever symp-
followed by 50 mg (<60 kg) or 75 mg (>60 kg) daily tomatic either in the form of intense headache with
and SULF 4 g daily in four divided doses on all days. ophthalmoscopic demonstration of papilloedema
All patients were given oral folinic acid supplementa- (4/41 patients) or seizures in the setting of radiographic
tion (15 mg four times weekly). Curative therapy was intracranial toxoplasmic abscess with perlesional
given for 4–6 weeks according to the response; 25 mg of oedema (all 7/41 patients) were treated with short
PYR once daily and 500 mg of SULF four times daily courses of either systemic dexamethasone or mannitol
was continued as maintenance therapy along with infusion in standard doses.
HAART till CD4 rose above 200/mL.4 There was no difference between pre-treatment CD4
CTX-CLD consisted of TMP (20 mg/kg/day) counts (81.44  18.58/mL for PYR-SULF vs. 83.12 
plus SMX at a fixed ratio of 1:5 given orally (two 16.54/mL for CTX-CLD, p value ¼ 0.76) among the
double strength [DS] tablets bid in adults) and oral groups.
CLD 600 mg thrice daily. After 4–6 weeks, HAART Comparison of treatment outcomes is detailed in
was started in accordance with National guidelines Table 1.
along with suppressive maintenance therapy (TMP- In PYR-SULF group, complete response occurred
SMX 1 DS tablet bid and CLD 300 tid) till CD4 rose in 5/16 patients (31.25%, 95% Confidence interval
above 200/mL after which maintenance therapy was [95% CI]: 14.16–55.60) and partial response in 4/16
withdrawn. (25%, 95% CI: 10.18–49.50). Seven patients out of

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Goswami et al. 3

Table 1. Comparison of baseline parameters, clinical details and treatment outcomes between treatment
groups.

Parameters CC1 (n ¼ 16) CC2 (n ¼ 25) p value

Mean age in years (standard deviation) 29.81 (8.21) 33.40 (7.36) 0.15
Male gender (%) 14 (87.5) 19 (76) 0.45
Risk factors for AIDS
Intravenous drug abuse (%) 1 (6.25) 2 (8) 1.00
Heterosexual contact (%) 12 (75) 19 (76) 1.00
Homosexual contact (%) 1 (6.25) 0 0.39
Blood transfusion (%) 3 (18.75) 4 (16) 1.00
Mean CD4 counts per mL (standard deviation) 81.44 (18.58) 83.12 (16.54) 0.76
Clinical characteristics
Fever (%) 11 (68.75) 11 (44) 0.19
Headache (%) 10 (62.5) 14 (56) 0.75
Seizures (%) 3 (18.75) 4 (16) 1.00
Other focal neurodeficit (%) 10 (62.5) 16 (64) 1.00
Opportunistic infections
Pulmonary tuberculosis with or without dissemination 4 (25) 8 (32) 0.73
Oral with or without oesophageal candidiasis 8 (50) 10 (40) 0.75
Visceral leishmanisis 2 (12.5) 0 0.15
Pneumocystis jirovecii pneumonia 2 (12.5) 4 (16) 0.64
Herpes zoster 1 (6.25) 3 (12) 1.00
Cryptococcal meningitis 1 (6.25) 0 0.39
Protozoal diarrhoea 1 (6.25) 3 (12) 1.00
Treatment response
Complete response 5 (31.25) 20 (80) 0.003
Partial response 4 (25) 2 (8) 0.187
Treatment failure 7 (43.75) 3 (12) 0.03
CC1: combination chemotherapy consisting of pyrimethamine and sulphadiazine; CC2: combination therapy consisting of
cotrimoxazole and clindamycin.

sixteen (43.75%, 95% CI: 23.10–66.82) in PYR-SULF PYR-SULF group and the difference attained statistical
group had treatment failure. Two died while on treat- significance with a p value of 0.002 (relative risk [RR]
ment and five developed severe drug toxicities leading 2.56, 95% CI: 1.21–5.43). We compared the difference in
to withdrawal of therapy. Major bleeding occurred in proportions of patients attaining some response to ther-
four and Stevens-Johnson syndrome developed in one apy defined as rate of occurrence of complete and
(who was subsequently lost to follow-up). All four partial response. Some response was present in 88%
patients with major bleeding subsequently died. (22/25, 95% CI: 70.04–95.83) in CTX-CLD group com-
In the CTX-CLD group, complete response pared to 56.2% (9/16, 95% CI: 33.18–76.9) in PYR-
occurred in 20/25 patients (80%, 95% CI: 60.87– SULF group (p ¼ 0.02, RR 1.564, 95% CI 0.99–2.47).
91.14), partial response in 2/25 patients (8%, 95% CI: Overall, nine patients died while on treatment – six
2.22–24.97). Three patients (12%, 95% CI: 4.17–29.96) patients in PYR-SULF group and three patients in
died on treatment. No major toxicity occurred: two CTX-CLD group. There was a trend towards higher
patients had minor dermatological complications and on-treatment mortality in PYR-SULF group in com-
four had non-dermatological complications comprising parison to CTX-CLD group (mortality rates 37.5% in
asymptomatic reversible neutropenia (3/25, 12%, 95% PYR-SULF vs 12% in CTX-CLD group, p
CI: 4.17–29.96) and diarrhoea (1/25, 4%, 95% CI: value ¼ 0.07, RR ¼ 3.125, 95% CI: 0.91–10.75).
0.71–19.54) responding to oral metronidazole therapy. Distribution of major toxicities is given in Table 2.
Efficacy-wise complete response occurred in 80% Overall 62.5% (10/16, 95% CI: 38.64–81.52) of patients
(20/25, 95% CI: 60.87–91.14) in CTX-CLD group com- in PYR-SULF suffered from some drug-related adverse
pared to 31.25% (5/16, 95% CI: 14.16–55.60) in reactions whereas only 24% (6/25, 95% CI: 11.5–43.43)

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4 International Journal of STD & AIDS 0(0)

Table 2. Distribution of major toxicities (Fischer’s exact test).
Toxicity
Skin rash
Asymptomatic reversible
neutropenia
Febrile neutropenia
Steven-Johnson syndrome
Severe thrombocytopenia
and major bleeding
Diarrhoea
Overall complications
CC1: combination chemotherapy consisting of pyrimethamine and
sulphadiazine; CC2: combination therapy consisting of cotrimoxazole
and clindamycin.
of patients in CTX-CLD groups had adverse drug reac-
tions (p ¼ 0.02, RR ¼ 2.60, 95% CI: 1.17–5.76). The
commonest complication in PYR-SULF group was
severe thrombocytopenia with major bleeding that
occurred in 25% of patients (4/16, 95% CI: 10.18–
49.5), who subsequently died. None of the patients in
CTX-CLD group had severe thrombocytopenia or
major bleeding and the difference in frequency of occur-
rence of bleeding between two treatment groups was
statistically significant (p value ¼ 0.01).
Four surviving patients in PYR-SULF group with
partial response to PYR and SULF were ultimately
treated with CTX and CLD combination (not included
among the 25 patients of CTX-CLD group). All of
them attained complete response.
Discussion
Cerebral toxoplasmosis in immunocompromised
patients is fatal, if left untreated.6 The usual dismal
prognosis of pre-HAART era7 has been improved
with reduction of incidence of cerebral toxoplasmosis
after worldwide introduction of HAART.8 Because
relapse occurs in as many as 80% of cases,9 combin-
ation chemotherapy in prolonged duration followed by
secondary prophylaxis has been advocated.2,4
The classical therapy for cerebral toxoplasmosis has
been PYR plus SULF plus leucovorin (level of evidence
[LOE] AI).2 Leucovorin reduces the likelihood of the
hematologic toxicities associated with PYR ther-
apy.10,11 The preferred alternative regimen is PYR
plus CLD plus leucovorin (LOE AI).2,12 Treatment
with TMP-SMX has been considered an option (LOE
BI) in CDC guidelines.2 Other regimens with some
activity against cerebral toxoplasmosis are atovaquone
plus either PYR or SULF (LOE BII);13 azithromycin
plus PYR (LOE BII);14 clarithromycin plus PYR (LOE
CC–1 CC–2
(n ¼ 16) (n ¼ 25)
1 2
3 3
1 0
1 0
4 0
0 1
10 6 0.02
CIII);15 5-fluorouracil plus CLD (LOE CIII);16 dap-
sone plus PYR (LOE CIII)17 and minocycline or doxy-
cycline with PYR, SULF or clarithromycin (LOE
p Value
CIII).18 Side effects may develop in as many as 40%
1.00 of patients often requiring treatment discontinuation.4
0.66 Most of the regimens are PYR-based. It is pertinent
to mention that there have been no studies demonstrat-
0.39 ing superior efficacy of PYR/SULF therapy over other
0.39 regimens. Atovaquone was the only drug that have been
0.01 shown to be inferior but bearing the caveat that this
result originated because atovaquone was not adminis-
1.00 tered correctly during a meal.19 Complete response rates
in PYR-SULF-based regimen has been reported to vary
from 55% to 65% in European and North American
studies.1,3,20 Two recent and albeit smaller reports, from
Africa and China, showed disappointingly low response
rates in the order of 30–40%.21,22 The major and often
restrictive obstacle for this regimen has been develop-
ment of toxicity. At least one drug-related-toxicity was
manifested in almost 60–70% of patients in most of the
clinical studies related to cerebral toxoplasmosis treated
with PYR-SULF.1,12,19 In around 30% of patients these
toxicities were dose-limiting and resulted in treatment
withdrawal or switch to alternative regimens.1,12,20,22
On-treatment death occurred in 5–15% of patients trea-
ted with PYR and SULF.1,12,20,21,22 It is worthwhile to
recall the results of Katlama et al.1 who reported their
experience of treating cerebral toxoplasmosis with PYR
and SULF in 147 patients, which is the largest cohort till
now. They reported a complete response of 65%, partial
response of 21%, overall toxicity in 65%, toxicity
amounting to treatment withdrawal in 29.93% and
on-treatment death in 15% of patients treated with
PYR and SULF. Interestingly in this study almost
one-third of the patients originally treated with PYR-
SULF combination had to withdraw their therapy due
to significant toxicity (29.93%, 44/147) and had to be
switched over to the second treatment arm. However
while analysing the efficacy the authors included these
44 patients as treatment responders.1,6 The details of
these parameters of Katlama et al.1 and other studies
on cerebral toxoplasmosis are displayed in Table 3.
Despite an acceptable level of efficacy, the burden of
toxicity in PYR-based regimens puts the onus on draw-
ing to surface alternative regimens that can match
standard regimen in terms of efficacy and outperform
in terms of safety. The only regimen devoid of PYR
with acceptable level of evidence is CTX.
Two different groups compared CTX monotherapy
with PYR SULF (PS) combination. In 1998, Torre
et al.3 considered CTX in cerebral toxoplasmosis as
an alternative agent in 77 patients. Good clinical
response was equally common (70%) in both CTX
arm and PS arm as was radiological response (CTX
arm vs PS respectively: 68% vs. 62%; RR 1.09; 95%

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Goswami et al. 5

Table 3. Response rates, toxicity and on-treatment mortality of patients of cerebral toxoplasmosis on pyrimethamine sulphadiazine
regimen: results of various studies.

Some response Toxicity requiring

Complete (both complete Overall treatment On treatment
Studies response Partial response and partial) toxicity withdrawal mortality
1
Katlama et al. 55% (81/147) 21% (31/147) 75% (112/147) 65% (96/147) 29.93% (44/147) 15% (22/147)
3
Torre et al. 65.7% (23/35) 20% (7/35) 85.7% (30/35) 21.6% (8/37) 2.37% (1/37)
Dannemann et al.12 48.5% (16/33) 58% (19/33) 33.33% (11/33) 6% (2/33)
Leport et al.20 58% (14/24) 51.66% (10/24) 71% (25/35) 28.57% (10/35) 11.42% (4/35)
Arens et al.21 39% (7/18) 50% (9/18) 89% (16/18) 22% (4/18) 11% (2/18)
22
Kongsaengdao et al. 30% (6/20) 35% (7/20) 5% (1/20)

CI 0.78–1.51). However, tolerability was significantly infection and prospective studies are needed in the set-
better in the CTX group.3 Beraud et al.,5 in a retro- ting of cerebral toxoplasmosis treated with CTX-CLD
spective study in 2006, claimed CTX monotherapy to to determine the risk benefit ratio of CLD use.
be effective in 85.5%, with a relatively low incidence of Notably there is a trend towards less mortality in
side effects (22%; 7.4% requiring treatment interrup- CTX-CLD as compared to standard regimen of PYR-
tion). It is interesting to note that their reported efficacy SULF though the difference did not attain statistical
was palpably higher than previous reports. significance (12% vs. 37.5%, p value 0.063, RR 0.09,
Initially CLD was found to be effective against 95% CI: 0.09–1.1).
Toxoplasma in murine models.23,24 Later it was used We used both steroids and mannitol for emergent
in cerebral toxoplasmosis in combination with PYR. management of cerebral oedema as an adjunct to
Danneman et al.12 assessed 59 patients of cerebral toxo- definitive antimicrobial therapies in 11 out of 41
plasmosis out of which, 26 received PYR and CLD patients. Though treatment of cerebral oedema in the
(PC) and 33 patients received PS. Complete or partial justified setting is often life-saving, in the context spe-
resolution was equally common between the groups cifically of cerebral toxoplasmosis the survival benefit
(46.2% in PC vs. 48.5% in PS; RR 0.95; 95%CI of the same could not be established in a recent retro-
0.55–1.64). Radiological response was slightly better spective analysis despite adequate demonstration of
in PC group (73% vs. 61%; RR 1.21; 95%CI 0.84– safety.25 Prospective studies are warranted for the elu-
1.73). Sixteen (62%) patients in PC and 19 (58%) cidation of the exact role of anti-oedema measures in
patients in PS experienced adverse events (RR 1.07; this setting.
95%CI 0.7–1.63).12 Similar results were also reported Limitations of the present study were retrospective
by Katlama et al.1 nature and small sample size.
Ours is the first study reporting CLD in combination We propose that the new combination chemother-
with TMP-SMX. Efficacy wise this combination regi- apy, which is widely available, effective and safe, may
men (CTX-CLD) is superior compared to PYR-SULF be practiced in developing countries and the present
(80% vs. 31.25% respectively, p value 0.002). As TMP– study warrant further prospective randomised trials
SMX (a folate metabolism inhibitor) and CLD (inhibi- for definitive evaluation of this approach.
tor of translation in the apicoplast of T. gondii) have
different mechanisms of action,4 this combination ther-
Acknowledgements
apy possibly offers mechanistic advantage over PYR-
based therapy. We are thankful to the Director and staff of School of
Adverse effects were less common in CTX-CLD Tropical Medicine and IPGMER, Kolkata, for their co-
operation and support.
group (24% vs 62.5%, RR 2.60, 95% CI: 1.17–5.76).
Severe bleeding episodes, as adverse effect of PYR-
SULF, were absent in CTX-CLD regimen. Diarrhoea Conflict of interest
is a known side-effect of CLD, but it occurred in only The authors declare no conflict of interest.
one of our patients. That episode lasted for three days
and the patient received oral metronidazole therapy
empirically for the same. It did not amount to treat- Funding
ment interference or withdrawal. However, use of CLD This research received no specific grant from any funding
is wagered with the possibility of Clostridium difficile agency in the public, commercial, or not-for-profit sectors.

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6 International Journal of STD & AIDS 0(0)

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