Toxoplasmic encephalitis relapse rates with pyrimethamine-based therapy: systematic review and meta-analysis

Figures & data

Figure 1. Search flow diagram.

Table 1. Summary of study characteristics performed until 1996.

Author	Study Design	Demographics	Pyrimethamine-based therapy		No. patients evaluated for relapse, n	Relapse, n(%)	Follow-up
			Acute	Maintenance
Randomized studies
Katlama (1996)	Randomized prospective open-label	N = 299	PS	PS	PS: 83	PS: 17 (20.5%)	89 to >130 weeks
		PC (n = 152)	PYR (50 mg daily) plus SDZ (4 g daily in four divided doses) plus folinic acid (min 50 mg/wk)	PYR (25 mg/day) plus SDZ (500 mg four times/day) plus folinic acid 50 mg weekly	PC: 92
						PC: 35 (38.0%)
		Male:133 (88%)
		Mean age: 34 yrs
		PS (n = 147)
		Male: 129 (88%)		PC
				PYR (25 mg/day) plus CLI (300 mg four times/day) plus folinic acid 50 mg weekly
		Mean age: 33 yrs
			PC
			PYR (50 mg daily) plus clindamycin (2.4 g daily in four divided doses) plus folinic acid (min 50 mg/wk)
				Maintenance therapy was life-long.
			Acute therapy was given for six weeks.
Podzamczer (1995)	Randomized open-label	N = 105	n.a.	Daily PS	105	Total: 11 (10.4%)	median 11 months
		Daily: (n = 60)		PYR (25 mg/day) plus SDZ (500 mg four times per day) and folinic acid (15 mg/day).
		Male: 40 (66.7%)				Intermittent: 19.5 per 100 patient-yrs
		Age: 34 yrs
		Twice weekly: (n = 45)
				Intermittent PS
		Male: 34 (75.6%)				Daily: 4.4 per 100 patient-yrs
				PYR (25 mg/day) twice weekly plus SDZ (500 mg four times per day) and folinic acid (15 mg/day).
		Age: 32 yrs
Torre (1998)	Randomized, prospective, pilot	N = 77	PS	Same regimens as above but at half of the original dosage given for three months	PS: n = 35	PS: 0	3 months
		PS (n = 37)	PYR (50 mg/day) plus SDZ (60 mg/kg/day) plus folinic acid (10 mg/day)			TMP-SMX: 1 (2.7%)
					TMP–SMX: n = 37
		Male: 29 (78.4%)
		Mean age: 32.4 yrs
		TMP-SMX (n = 40)
			TMP-SMX
		Male: 28 (70%)	TMP (10 mg/kg/day BID) plus SMX (50 mg/kg/d BID)
		Mean age: 34.0 yrs
			TX was for 30 days
Prospective studies
Bouree (1997)	Prospective observational	N = 60	PS	PS	60	11 (18.3%)	7 years
		Male: 46 (76.7)	PYR (100 mg/day) plus SDZ (6 g/day) plus folinic acid (50 mg/day)	PYR (100 mg/day) plus SDZ (6 g/day) plus folinic acid (50 mg/day)
		Mean age: 40 yrs.
Canessa (1992)	Prospective	N = 24	TMP-SMX	PYR±SMP	24	4 (17%)	n.r.
		Male: 19 (79.2%)	TMP-SMX (40 mg/kg/day) or TMP-SMX (120 mg/kg/day)	Sulfamethoxpyrazine (500 mg) plus PYR (25 mg) twice weekly
		Age, range: 23–53 yrs
			Folinic acid (15 mg/day) was also given
			TX duration 25 day
Leport (1987)	Prospective observational	N = 12	PS	Same as acute	12	0	n.r.
		Male: 11 (91.7%)	PYR (average 50 mg [range 15–100 mg) plus SDZ (average 4 g (range 2–6 g), for 30 days. Folinic acid (range, 5 to 50 mg/day) was also administered. The 12th patient died during TX
		Age, range: 20–47 yrs
Orefice (1992)	Prospective, observational	N = 15	PSC	PYR (25 mg/day) plus SDZ (2 g/day)	15	3 (20%)	n.r.
		Male: 12 (80%)	PYR (50 mg/day) plus SDZ (4 g/day) plus CLI (1200 mg/day) plus folinic acid
		PSC (n = 5)
		PS (n = 10)
			PS
			PYR (50 mg/day) plus SDZ (4 g/day) plus folinic acid
			TX was for 4–6 weeks
Ruf (1991)	Prospective, observational	N = 51	Three-drug regimen (PC ± SPY)	PYR ± SDX (Fansidar)	39	4 (10%)	Median 13 months
		Three-drug regimen (PC ± SPY) (n = 25)
		Two-drug regimen (PC) (n = 26)
				PYR (15 mg) plus SDX (500 mg) plus folinic acid (15 mg) twice a week.
			PYR (1.5 mg/kg/day) plus CLI (2400 mg/day) plus SPY (9 × 10^6 IU/day)
			Two-drug regimen (PC)
			PYR (50 mg/day for body weight <65 kg or 75 mg/day for body weight >65 kg) plus CLI
			(2400 mg/day)
			Both TX arms received folinic acid 45 mg/day (although some patients only received drug after myelosuppression became apparent)
			TX was for three weeks
Ruf (1993)	Prospective, open-label	N = 56	PC	PYR ± SDX (Fansidar)	56	4 (7.1%)	n.r.
		Male: 48 (85.7%)	PYR (50 mg/day body weight <65 kg or 75 mg/day body weight >65 kg) plus CLI (2400 mg/day) plus LEU 30 mg/day.
				25 mg PYR/SDX 500 mg plus LEU (15–30 mg) twice a week
		Median age: 39 yrs
Retrospective studies
Altes (1989)	Retrospective	N = 70; 13 with TE	PS	PYR 25 mg/day	13	7 (54%)	n.r.
			PYR (50–100 mg) plus SDZ (4–6 g) and folinic acid (15–45 mg) daily.
Dannemann (1988)	Retrospective, case review	N = 15	CLI	PC	PC: 4	PC: 1 (25%)	Mean 7.5 months
		Mean age:47 yrs	Various IV dosages of CLI (–) from 1200–4.8 g/day given from every 6-8 h)	PYR (25–75 mg/day plus CLI (300 to 900 every 6-8 h) or PYR (75 mg every other day) plus CLI 450 mg every 6 h)	PYR: 4
						PYR: 1 (25%)
		CLI (n = 9)			CLI: 3
					SPY: 1	CLI: 3 (100%)
		PC (n = 6)
						SPY: 0
			PC
			Various IV dosages of CLI (–from 1200–4.8 g/day given every 6-8 h) with PYR (25–100 mg/day)
				PYR
				PYR (25–100 mg/day)
				CLI
				CLI (300–450 mg every 6 h or 900 every 8 h)
			Folinic acid (5–10 mg/day) was administered to 11 patients	SPY
				SPY (500 mg every 8 h)
			TX length variable across patients (range 3 to 300 days)
de Gans (1992)	Retrospective	N = 38	PS	PYR (25 or 50 mg/day) plus folinic acid (15 mg/day)	38	12 (31.6%)	n.r.
		Male: 37 (97.7%)	PYR (25–75 mg/day) plus SDZ (2–6 mg/day) plus folinic acid (15 mg/day)
		Median age: 38.5
			Acute treatment was for six weeks.
Ferrer (1996)	Retrospective	N = 63	PS	PS	63	Total: 19 (30.2%)	n.r.
		Male: 46 (73%)	PYR (50–75 mg/day) plus	PYR (25 mg/day) plus SDZ (2 g/day)
		Mean age for both: 21–65 years				PS: 12
			SDZ (4 g/day) plus folinic acid (15 mg/day) QID PO for 4–6 weeks	PC		PC: 7
				PYR (25 mg/day) plus CLI (1200 mg/day)
		PS (n = 49)
		PC (n = 14)
			PC (n = 14)
			PYR (50–75 mg/day) plus folinic acid (15 mg/day) QID PO for 4–6 weeks plus CLI (600 mg/q6 h) PO or IV
			Pts w/ intracranial hypertension and perilesional edema:
			Dexamethasone (12- 16 mg/day)
Foppa (1991)	Retrospective	N = 14	PC	PC	14	0	Mean 7.7 months
		Male: 13 (92.9%)	PYR (100 mg loading dose, followed by 50 mg/d) plus CLI (600–900 mg orally TID) plus folinic acid (15 mg/day) for 6–8 weeks	PYR (25 mg/d) plus CLI (300 mg QID or 450 mg TID) plus folinic acid (15 mg/day)
		Age, range: 29–39 yrs
			Duration of acute therapy was from 6 to 8 weeks
Gonzalez-Clemente (1990)	Retrospective	N = 57	PS	PS	PS: n = 15	PS: 0	PS: Median 12.3 months
			PYR 5–100 mg for one day followed by 25–50 mg/day, SDZ 75 mg/kg/day divided into four doses, plus folinic acid (10–20 mg/day)	PYR 5–100 mg for one day followed by 25–50 mg/day, SDZ 75 mg/kg/day divided into four doses, plus folinic acid (10–20 mg/day) two days per week (Tuesday and Friday)		PC: 4 (40%)
					PC: n = 10
							PC: Median 13.3 months
			PC
			If patient had sulfa allergy, clindamycin (600 mg/every 6 h) was substituted for SDZ.
				PC
				If patient had sulfa allergy, clindamycin (600 mg/every 6 h) was substituted for SDZ
			Acute treatment was for 3 to 6 weeks
Leport (1988)	Retrospective chart review	N = 35	PS	PS	24	6 (25%)	Mean 6 months
		Male: 33 (94.3%)	PYR (loading doses 100–200 mg for first 1–2 days, followed by 50–100 mg/day) plus SDZ (2–6 g/day) plus folinic acid (5–50 mg/day)	PYR (25–50 mg/day) plus SDZ (1–4 g/day) plus folinic acid (5–50 mg/day)
		Mean age: 37.0 yrs
Leport (1991)	Retrospective	N = 35	n.a.	PS (n = 13)^a	35	Total: 6 (17%)	Mean 13 months
						PC: 4
						PYR: 1
				PYR (25–100 mg/day) plus SDZ (2–4 g/day)
						PS: 1
				PC (n = 20)^a PYR (25–100 mg/day) plus CLI (450–1200 mg/day)
				PYR (n = 11)^a
				PYR 50–100 mg/day
Pedrol (1990)	Retrospective	N = 43	PS	PS	12	6 (50.0%)	10.3–13.7 months
		Male: 35 (81.4%)	PYR 50–75 mg loading dose, followed by 25 mg/day plus SDZ 75 mg/day plus folinic acid (10–20 mg/day)	Same as acute dosage but given only 2 days/wk (Tues and Fri)
			Acute treatment was for 3 weeks
Ragnaud (1993)	Retrospective	N = 73	PS	PS	60	12 (20%)	8 months
		Sex ratio: 2.8:1	PYR (100–200 mg/day for 1–3 days followed by 75 mg/day) plus SDZ (4–8 g/day) plus folinic acid (10–50 mg/day)	PYR 50 mg / day plus SDZ 2 to 3 g / day
		Mean age: 36.2 yrs
				PC
				PYR 50 mg/day plus CLI 1.2 g/day
Renold (1992)	Retrospective chart review	N = 86	PS	PS	82	16 (19.5%)	n.r.
		Male: 69 (80%)	PC	PC
			Acute treatment was defined as antitoxoplasma drugs received within 42 days of diagnosis	Maintenance therapy was calculated from the 42nd day following diagnosis to death, loss to follow-up, relapse, or December 31, 1990, or whichever came first.
		Mean age: 36.4 yrs

^a n indicates number of courses. Forty-four treatment courses were evaluated in 35 patients.

BID: twice daily; CLI, clindamycin; IV, intravenous; LEU, leucovorin; n.a., not applicable; n.r., not reported; PC, pyrimethamine plus clindamycin; PK, pharmacokinetic; PS, pyrimethamine plus sulfadiazine; PSC: pyrimethamine plus sulfadiazine, plus clindamycin; PYR, pyrimethamine; QID, four times/day; SDX, sulfadoxine; SDZ, sulfadiazine; SMP, sulphamethoxpyrazine; SMX, sulfamethoxazole; SPY, spiramycin; TMP, trimethoprim; TMP-SMX, trimethoprim-sulfamethoxazole (co-trimoxazole); TX, treatment.

Table 2. Summary of study characteristics after 1996.

Author	Study design	Demographics	Pyrimethamine-based therapy		No. patients evaluated for relapse, n	Relapse, n(%)	Follow-up
			Acute	Maintenance
Randomized studies
Chirgwin (2002)	Randomized, open-label, phase 2	N = 39	ATO ± PYR	42 weeks after acute treatment with same treatment regimen as acute therapy	15	1 (6.7%)	48 weeks
		ATO±PYR (n = 28)
			ATO (1500 mg BID) plus PYR (200 mg loading dose, followed by 75 mg/day) plus LEU 10 mg daily
		Male: 22 (79%)
		Median age: 35 yrs
		ATO±SDZ (n = 12)
		Male: 10 (83%)
		Median age: 37 yrs
			ATO ± SDZ
			ATO (1500 mg BID) plus SDZ (1500 mg QID) plus LEU 10 mg/day.
			Acute treatment was administered for six weeks
Podzamczer (2000)	Randomized open-label	N = 124	n.a.	PS Daily Regimen:PYR	124	Total: 16 (12.9%)	Median 11 months
						Daily: 14.9 episodes per 100 patient yrs
				(25 mg/day) plus SDZ (1 g BID) plus folinic acid (15 mg/day)
		Daily (n = 58)
		Male/female ratio: 3.5
						Intermittent: 14.1 episodes per 100 patient yrs
		Age: 35.7 yrs
		Thrice weekly (n = 66)		PS Three times/wk regimen:
		Male/female ratio:5.0		PYR (50 mg/day) plus (SDZ: 1 g BID) plus folinic acid (15 mg)/day
		Age: 34.9 yrs.
Prospective studies
Langmann (2004)	Prospective	N = 6 (3 received secondary prophylaxis)	n.a.	PYR: 50 mg/day or 37.5 mg/day depending on body weight plus folinic acid (7.5 mg/day)	3	0	Mean 22 ± 13 months
		Age, range: 35–59 yrs
Vidal (2005)	Prospective longitudinal	N = 55	PS	PS	46	2 (4%)	One year from diagnosis
		Male: 33 (60%) Mean age:	PYR + SDZ + folinic acid	PYR + SDZ + folinic acid
		36 yrs
Retrospective study
Arendt (1999)	Retrospective	N = 106	P ± SND	PYR: 75 mg/day	106	13 (12%)	n.r.
		Male: 101 (95.3%)	PYR (75 mg/day) plus sulfonamides (2 g/day) or clindamycin (2400 mg/day).
		Mean age: 40.4 yrs
		P ± SND (n = 98)
		PC (n = 6)
			PC
			PYR (75 mg/day) plus clindamycin (2400 mg/day).
Davarpanah (2007)	Retrospective	N = 38	PS	PS	4	0	n.r.
		Male: 30 (78.9%)	PYR + SDZ + leucovorin	PYR + SDZ
		Age: 38 yrs

ATO, atovaquone; LEU, leucovorin; n.a., not applicable; n.r., not reported; PC, pyrimethamine plus clindamycin; PS, pyrimethamine plus sulfadiazine; P + SND, pyrimethamine plus a sulfonamide; PYR, pyrimethamine; SDZ, sulfadiazine.

Table 3. Pyrimethamine-based maintenance therapy: relapse rates in pre-HAART and post-HAART period.

	Proportions Fixed-effect	Proportions Random-effect	I^2
Pre-HAART	0.192 (95% CI = 0.167 to 0.218)	0.189 (95% CI = 0.137 to 0.247)	76.4% (95% CI = 62.8 to 83.5%)
Post-HAART	0.111 (95% CI = 0.078 to 0.149)	0.111 (95% CI = 0.078 to 0.149)	0% (95% CI = 0 to 61%)
Intermittent Pre-HAART	0.209 (95% CI = 0.139 to 0.287)	0.256 (95% CI = 0.104 to 0.445)	72.9% (95% CI = 17.9 to 86.7%)
Intermittent Post-HAART^a	–	–
Continuous Pre-HAART	0.187 (95% CI = 0.161 to 0.214)	0.173 (95% CI = 0.119 to 0.234)	77.5% (95% CI = 64.4 to 84.3%)
Continuous Post-HAART	0.105 (95% CI = 0.069 to 0.146)	0.105 (95% CI = 0.069 to 0.146)	0% (95% CI = 0 to 61%)

^a Analysis was not performed as only one study in the post-HAART timeframe evaluated intermittent pyrimethamine-based therapy.

CI, confidence interval; I², inconsistency.

Figure 2. Forest plot of fixed for analysis of pre-HAART studies.

Figure 3. Forest plot of random effect model for analysis of pre-HAART studies.

Figure 4. Forest plot of (A) fixed and (B) random effect model for analysis of post-HAART studies.

Figure 5. Funnel plot analysis of reporting bias.