Alternative treatment approach to cerebral toxoplasmosis in HIV/AIDS: experience from a resource-poor setting

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 have had to use the combination of two effective alternative agents for toxoplasmosis, cotrimoxazole and clindamycin, on compassionate grounds. This retrospective observational study reports superior efficacy and better tolerability of cotrimoxazole/clindamycin compared to the 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 with cotrimoxazole/clindamycin than with pyrimethamine/sulfadiazine group (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 the pyrimethamine/sulfadiazine group in comparison to the cotrimoxazole/clindamycin (mortality rate 37.5% in pyrimethamine/sulfadiazine vs 12% in cotrimoxazole/clindamycin, p = 0.07, relative risk = 3.125, 95% confidence interval: 0.91–10.75). Overall, 62.5% (10/16) of patients on pyrimethamine/sulfadiazine suffered drug-related adverse reactions compared to 24% (6/25) on cotrimoxazole/clindamycin (p = 0.02, relative risk = 2.60, 95% confidence interval: 1.17–5.76). The commonest complication of 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 used in developing countries.

Keywords

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

Introduction

Cerebral toxoplasmosis is the most common opportunistic infection of the central nervous system in people living with HIV/AIDS.¹ The current recommended treatment consists of the combination chemotherapy with pyrimethamine (PYR) and sulfadiazine (SULF).² The most significant problem of this combination chemotherapy is poor tolerability, high rates of adverse effects and drop outs. Cotrimoxazole (CTX) has been shown to be an acceptable alternative with comparable efficacy as has been PYR-clindamycin (CLD) combination therapy.³

We started to use the combination of the two effective alternative drugs for toxoplasmosis, CTX and CLD, on compassionate grounds as PYR was only irregularly available in West Bengal, India, either in the commercial market or from Government sources. It is worthwhile to mention that a lot of third-world countries use trimethoprim (TMP)/sulphamethoxazole (SMX) for cerebral toxoplasmosis because SULF is far too expensive and SULF availability is also irregular in certain global regions like Italy (unpublished data). We report in this retrospective observational study the superior efficacy and better tolerability of TMP-SMX- CLD combination chemotherapy for the treatment of cerebral toxoplasmosis.

Materials and methods

We retrospectively reviewed the hospital records of AIDS patients with a first episode of cerebral toxoplasmosis who were admitted under our care at the School of Tropical Medicine and Institute of Post Graduate Medical Education and Research, Kolkata, India, in the past 4 years (January 2009 to January 2013). The investigators' clinical records of patients managed under their care at inpatient and outpatient departments were analysed anonymously with permission from the appropriate authorities. Waiver of approval was granted by the Clinical Research Ethics Committee, Calcutta School of Tropical Medicine, Kolkata.

Cerebral Toxoplasmosis was diagnosed in 41 HIV-seropositive patients in this study with three parameters

Clinical symptoms (fever, headache, focal neurologic deficits),

Computed tomography (CT), MRI findings (ring-enhancing lesions),

Positive toxoplasma IgG antibody.

Patients were treated with combination chemotherapy consisting of either pyrimethamine with sulfadiazine (PYR-SULF) or cotrimoxazole and clindamycin (CTX-CLD). Informed consent was taken for all patients before starting CTX-CLD.

PYR-SULF consisted of PYR 200 mg on 1st day followed by 50 mg (<60 kg) or 75 mg (>60 kg) daily and SULF 4 g daily in four divided doses on all days. All patients were given oral folinic acid supplementation (15 mg four times weekly). Curative therapy was given for 4–6 weeks according to the response; 25 mg of PYR once daily and 500 mg of SULF four times daily was continued as maintenance therapy along with HAART till CD4 rose above 200 cells/µL.⁴

CTX-CLD consisted of TMP (20 mg/kg/day) plus SMX at a fixed ratio of 1:5 given orally (two double strength [DS] tablets bid in adults) and oral CLD 600 mg thrice daily. After 4–6 weeks, antiretroviral therapy (ART) was started in accordance with National guidelines along with suppressive maintenance therapy (TMP-SMX 1 DS tablet bid and CLD 300 tid) till CD4 rose above 200 cells/µL after which maintenance therapy was withdrawn.

As described in a previous study, response was defined clinically and by CT scan. 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. Partial response was defined as less than 50% improvement of clinical status and less than 50% decrease in the size of brain lesions after two weeks of treatment initiation. Treatment failure is defined as no improvement either clinically or radiologically; deterioration, except within first three days; death; major toxicity amounting to treatment withdrawal.⁵

Proportions were expressed as percentages and ratios. Continuous data were expressed as mean ± standard deviation. Categorical variables were compared using the Chi square test or Fischer’s exact test when Chi square test was not applicable. Continuous variables were compared with Students t test. All statistical analyses were performed using SPSS version 16.0 (SPSS Inc., Chicago, IL).

Results

Forty-one HIV patients with diagnosis of cerebral toxoplasmosis were admitted. Average age of the population was 32 ± 8.6 years (interquartile range [IQR]: 13). Thirty-three (80.48%) of them were men. One of them was on ART (second line regimen with tenofovir, lamivudine and atazanavir/ritonavir). Others were ART naive. Average CD4 count was 82.46 ± 17.15 cells/µL. Details of the baseline characteristics, clinical symptomatology, co-morbidities and treatment responses are given in Table 1.

Table 1.

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

Parameters	CC1 (n = 16)	CC2 (n = 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, cells per µL (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 leishmaniasis	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 sulfadiazine; CC2: combination therapy consisting of cotrimoxazole and clindamycin.

Sixteen patients received recommended first-line combination chemotherapy consisting of PYR-SULF. Twenty-five patients received combination therapy consisting of CTX-CLD. Cerebral oedema, whenever symptomatic either in the form of intense headache with ophthalmoscopic demonstration of papilloedema (4/41 patients) or seizures in the setting of radiographic intracranial toxoplasmic abscess with perilesional oedema (all 7/41 patients) were treated with short courses of either systemic dexamethasone or mannitol infusion in standard doses.

There was no difference between pre-treatment CD4 counts (81.44 ± 18.58 cells/µL for PYR-SULF vs. 83.12 ± 16.54 cells/µL for CTX-CLD, p value = 0.76) among the groups.

Comparison of treatment outcomes is detailed in Table 1.

In PYR-SULF group, complete response occurred in 5/16 patients (31.25%, 95% Confidence interval [95% CI]: 14.16–55.60) and partial response in 4/16 (25%, 95% CI: 10.18–49.50). Seven patients out of sixteen (43.75%, 95% CI: 23.10–66.82) in PYR-SULF group had treatment failure. Two died while on treatment and five developed severe drug toxicities leading to withdrawal of therapy. Major bleeding occurred in four and Stevens-Johnson syndrome developed in one (who was subsequently lost to follow-up). All four patients with major bleeding subsequently died.

In the CTX-CLD group, complete response occurred in 20/25 patients (80%, 95% CI: 60.87–91.14), partial response in 2/25 patients (8%, 95% CI: 2.22–24.97). Three patients (12%, 95% CI: 4.17–29.96) died on treatment. No major toxicity occurred: two patients had minor dermatological complications and four had non-dermatological complications comprising asymptomatic reversible neutropenia (3/25, 12%, 95% CI: 4.17–29.96) and diarrhoea (1/25, 4%, 95% CI: 0.71–19.54) responding to oral metronidazole therapy.

Efficacy-wise complete response occurred in 80% (20/25, 95% CI: 60.87–91.14) in CTX-CLD group compared to 31.25% (5/16, 95% CI: 14.16–55.60) in PYR-SULF group and the difference attained statistical significance with a p value of 0.002 (relative risk [RR] 2.56, 95% CI: 1.21–5.43). We compared the difference in proportions of patients attaining some response to therapy defined as rate of occurrence of complete and partial response. Some response was present in 88% (22/25, 95% CI: 70.04–95.83) in CTX-CLD group compared to 56.2% (9/16, 95% CI: 33.18–76.9) in PYR-SULF group (p = 0.02, RR 1.564, 95% CI 0.99–2.47).

Overall, nine patients died while on treatment – six patients in PYR-SULF group and three patients in CTX-CLD group. There was a trend towards higher on-treatment mortality in PYR-SULF group in comparison to CTX-CLD group (mortality rates 37.5% in PYR-SULF vs 12% in CTX-CLD group, p value = 0.07, RR = 3.125, 95% CI: 0.91–10.75).

Distribution of major toxicities is given in Table 2. Overall 62.5% (10/16, 95% CI: 38.64–81.52) of patients in PYR-SULF suffered from some drug-related adverse reactions whereas only 24% (6/25, 95% CI: 11.5–43.43) of patients in CTX-CLD groups had adverse drug reactions (p = 0.02, RR = 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 occurrence of bleeding between two treatment groups was statistically significant (p value = 0.01).

Table 2.

Distribution of major toxicities (Fisher's exact test).

Toxicity	CC–1 (n = 16)	CC–2 (n = 25)	p Value
Skin rash	1	2	1.00
Asymptomatic reversible neutropenia	3	3	0.66
Febrile neutropenia	1	0	0.39
Steven-Johnson syndrome	1	0	0.39
Severe thrombocytopenia and major bleeding	4	0	0.01
Diarrhoea	0	1	1.00
Overall complications	10	6	0.02

CC1: combination chemotherapy consisting of pyrimethamine and sulfadiazine; CC2: combination therapy consisting of cotrimoxazole and clindamycin.

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 the pre-ART era⁷ has been improved with reduction of incidence of cerebral toxoplasmosis after worldwide introduction of ART.⁸ Because relapse occurs in as many as 80% of cases,⁹ combination 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 haematologic toxicities associated with PYR therapy.^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 CIII);¹⁵ 5-fluorouracil plus CLD (LOE CIII);¹⁶ dapsone plus PYR (LOE CIII)¹⁷ and minocycline or doxycycline with PYR, SULF or clarithromycin (LOE CIII).¹⁸ Side effects may develop in as many as 40% of patients often requiring treatment discontinuation.⁴

Most of the regimens are PYR-based. It is pertinent to mention that there have been no studies demonstrating superior efficacy of PYR/SULF therapy over other regimens. Atovaquone was the only drug that have been shown to be inferior but bearing in mind that this result originated because atovaquone was not administered correctly during a meal.¹⁹ Complete response rates in PYR-SULF-based regimens have 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 development 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 treated 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.

Table 3.

Response rates, toxicity and on-treatment mortality of patients of cerebral toxoplasmosis on a pyrimethamine-sulfadiazine; regimen: results of various studies.

Studies	Complete response	Partial response	Some response (both complete and partial)	Overall toxicity	Toxicity requiring treatment withdrawal	On-treatment mortality
Katlama et al.¹	55% (81/147)	21% (31/147)	75% (112/147)	65% (96/147)	29.93% (44/147)	15% (22/147)
Torre et al.³	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)
Kongsaengdao et al.²²			30% (6/20)		35% (7/20)	5% (1/20)

Despite an acceptable level of efficacy, the burden of toxicity in PYR-based regimens puts the onus on drawing 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 an 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% CI 0.78–1.51). However, tolerability was significantly better in the CTX group.³ Beraud et al.,⁵ in a retrospective study in 2006, claimed CTX monotherapy to be effective in 85.5%, with a relatively low incidence of side effects (22%; 7.4% requiring treatment interruption). It is interesting to note that their reported efficacy was palpably higher than previous reports.

Initially CLD was found to be effective against Toxoplasma in murine models.^23,24 Later it was used in cerebral toxoplasmosis in combination with PYR. Danneman et al.¹² assessed 59 patients of cerebral toxoplasmosis, out of which 26 received PYR and CLD (PC) and 33 patients received PS. Complete or partial resolution was equally common between the groups (46.2% in PC vs. 48.5% in PS; RR 0.95; 95%CI 0.55–1.64). Radiological response was slightly better in PC group (73% vs. 61%; RR 1.21; 95%CI 0.84–1.73). Sixteen (62%) patients in PC and 19 (58%) patients in PS experienced adverse events (RR 1.07; 95%CI 0.7–1.63).¹² Similar results were also reported by Katlama et al.¹

Ours is the first study reporting CLD in combination with TMP-SMX. Efficacy wise this combination regimen (CTX-CLD) was superior compared to PYR-SULF (80% vs. 31.25% respectively, p value 0.002). As TMP–SMX (a folate metabolism inhibitor) and CLD (inhibitor of translation in the apicoplast of T. gondii) have different mechanisms of action,⁴ this combination therapy possibly offers mechanistic advantage over PYR-based therapy.

Adverse effects were less common in CTX-CLD 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 is a known side-effect of CLD, but it occurred in only 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 treatment interference or withdrawal. However, use of CLD is wagered with the possibility of Clostridium difficile infection and prospective studies are needed in the setting of cerebral toxoplasmosis treated with CTX-CLD to determine the risk:benefit ratio of CLD use.

Notably there is a trend towards less mortality in CTX-CLD as compared to standard regimen of PYR-SULF though the difference did not attain statistical significance (12% vs. 37.5%, p value 0.063, RR 0.09, 95% CI: 0.09–1.1).

We used both steroids and mannitol for emergent management of cerebral oedema as an adjunct to definitive antimicrobial therapies in 11 out of 41 patients. Though treatment of cerebral oedema in the justified setting is often life-saving, in the context specifically of cerebral toxoplasmosis the survival benefit of the same could not be established in a recent retrospective analysis despite adequate demonstration of safety.²⁵ Prospective studies are warranted for the elucidation of the exact role of anti-oedema measures in this setting.

Limitations of the present study were its retrospective nature and small sample size.

We propose that the new combination chemotherapy, which is widely available, effective and safe, may be used in developing countries and the present study warrants further prospective randomised trials for definitive evaluation of this approach.

Footnotes

Acknowledgements

We are thankful to the Director and staff of School of Tropical Medicine and IPGMER, Kolkata, for their co-operation and support.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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