primaquine double dose for seven days is inferior to single dose treatment for fourteen days in...
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Primaquine double dose for seven days is inferior to single dose treatment for fourteen days in preventing P. vivax relapses in Suriname
Stephen G.S. Vreden, Malti R. Adhin, Jeetendra Kumar Jitan, M. Sigrid Mac Donald Ottevanger, Gustavo Bretas
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P. Vivax treatment
Study question:
Is PQ double dose for 7 days as effective as 14 day standard dose?
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Study Design
En-blocque randomization in 2 groups Patients recruited from:
Kwamala Samutu, Amerindian Village in the south-west of Suriname
Paramaribo Malaria Center Group 1: 0.25mg/kg/day (15mg/day for 14
days) Group 2: 0.5mg/kg/day (30mg/day) for 7
days Follow up for at least 6 months
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Study Design Inclusion Criteria
Confirmed P.vivax (History of) fever
Exclusion Criteria
History of anti-malarial use in previous 2 weeks
Severe malaria Other severe disease Intolerance to anti-
malarial drugs Positive pregnancy test Known positive G6PD-
deficiency status
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Study Design (2)
At day 0, 14, and thereafter monthly follow up: Clinical evaluation Bloodsmear and dried bloodspot Binax NOW® (only at day 0, and at
recurring parasitaemia)
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Baseline characteristics of patientsGroup 1
(14 days)Group 2(7 days)
P-value
Number patients 28 34
Sexe M/F 17/11 24/10 0.414
Age (years) Mean (SD) Median Range
19.8 (11.2)21
2 to 43
31 (12.8)32
1 to 51
0.001
Weight (Kg) Mean (SD) Range Median
50.8 (21.3)11 to 83
58
64.2 (16.1)8.5 to 100
64
0.011
P < 0.05 indicates significant differences between variables in Students’s t test and Pearson’s chi-square
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Enrolment, exclusion and relapse frequency Group 1
(14 days)Group 2(7 days)
TotalP-
value
No. patients enrolled
33 51 84
No. patients evaluable#
28 34 62
Average follow-up 10.1
months7.8 months 0.015
Average time of recurring parasitaemia
3.8 months 4.1 months 0.832
Recurring parasitaemia
4(14.3%) 13(38.2%) 17 (27.4%) 0.035
# Patients excluded due to loss to follow up, protocol violation or other (in both groups 1 recurrent parasitaemia at month 1)
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Relapse rate
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 2 4 6 8 10 12 14
Time (months)
14 DAYS 7 DAYS
Pro
po
rtio
n r
elap
se f
ree
Kaplan Meier survival analysis of P. vivax relapses in patients treated with primaquine single dose for 14 days or double dose for 7 days
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Results
Higher incidence of recurrent parasitaemia in group 2 (38.2%; p <0.05)
14.3% relapse rate in group 1 suggests possible tolerance to PQ
2 recurrent parasitaemias in month 1 possible CQ tolerance
No difference in time of relapse
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Conclusion
PQ 0.5mg/kg/day for 7 days is inferior to standard regimen (0.25mg/kg/day for 14 days) of PQ therapy in Suriname
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Discussion
Small study population (n = 62) in this trial
Possibly a 1mg/kg/day PQ (60mg/day) regimen for 7 days should be investigated.
Because several patients traveled to endemic regions during the study, relapse could not be distinguished from reinfection
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Recent studies on primaquine short regimen
Krudsoord, S., Tangpukdee, N., Wilairatana, P., Phophak, N., Baird, J. K., Brittenham, G. M., and Looareesuwan, S., 2008. High-dose Primaquine Regimens against Relapse of Plasmodium vivax Malaria. Am J Trop Med Hyg 78 (5): 736-740.
Nguyen Van Hoang Dao, Bui Tri Cuong, and Nguyen Dang Ngoa, 1-24-2007. Vivax malaria preliminary observations following a shorter course of treatment with artesunate plus primaquine. Trans R Soc Trop Med Hyg 101: 534-539.
Both studies showed high efficacy of primaquine for seven days in doses of 30 mg and 22.5 mg respectively,…………….BUT
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Recent studies on primaquine short regimen, c’td.
Follow up in both studies was a mere 28 days, which may not be adequate to detect relapses.
Our relapses occurred at an average of 4 months.
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Recrudescence in P. falciparum
Genes with areas of well known genetic variety are: MSP1 MSP2 GLURP
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RECURRENT PARASITAEMIA IN P. vivax
Pv msp 1-F2 coding for merozoite surface protein 1
Pv msp3α coding for merozoite surface protein 3
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Recurrent parasitaemia in P.vivax
Identical patterns: reflecting the same genotype for the
tested gene region, suggesting relapse.
Difference in size and/or restriction pattern: may suggest a new infection, but a relapse
with a different genotype is also possible
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PROCEDURE Samples:
dag 0 & recurring: spotting of two drops of blood on filter paper (Whatman 3MM). .
Extraction of DNA:Plasmodium DNA extracted from both filters (Saponin-Chelex).
DNA Amplificatie:Both DNA samples : For both genes a master and an additional nested PCR
Repeatnumber Analysis: separation of DNA fragments by electrophoresis (horizontal/vertical agarose).
SNP Analyse: Restriction analysis (AluI, HhaI, MnlI) and separation on polyacrylamide slabgels.
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Repeatnumber
10 15 14a
AB A C
Pv MSP1F2 SIZE _
+
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4 5 6 7 8 9
RESTRICTIE ANALYSE AluI Pv MSP1F2
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PPQ code Datum afname Relapse DNA master F2 nested F2 Alu Mnl Typemaster MSP3
nested MSP3
Alu Hha I Type Opmerkingen CONCLUSIES
1 2 16-Oct-2006 D0 OK OK A b 2 Ab2 OK A b 2 Ab2 M2 = D0
2 2a 18-Dec-06 M 2 OK OK A b 2 Ab2 OK A b 2 Ab2
3 15 10-Nov-2006 D0 OK OK A c 2 Ac2 OK B c 3 Bc3 M2 = D0
4 15a 30-Jan-07 M 2 OK OK A c 2 Ac2 OK B c 3 Bc3
5 28 18-Jan-2007 D0 OK OK C r 17 Cr17 OK C j 7 Cj7 M4 = D0 Possible RECRUDESCENCE:
6 28a 22-May-07 M 4 OK OK C r 17 Cr17 OK C j 7 Cj7 Beide samples vertonen gelijke infectie:
7 51 24-Sep-07 D0 OK OK A b 2 Ab2 OK C i 9 Ci9 M2 = D0 2, 15, 28, 51, 58, 44, 63
8 51a 5-Dec-2007 M 2 OK OK A b 2 Ab2 OK C i 9 Ci9
9 58 30-Oct-2007 D0 OK OK A c 2 Ac2 OK A a 1 Aa1 M7 = D0
10 58a 20-May-2008 M 7 OK OK A c 2 Ac2 OK A a 1 Aa1
11 44 3-Jul-2007 D0 OK OK C t 16 Ct16 no - - - M4 = D0 (1 gene)
12 44a 12-Nov-2007 M 4 OK OK C t 16 Ct16 OK C i 9 Ci9
13 63 21-Dec-2007 D0 OK OK C r 16 Cr16 no - - - - M3 = D0 (1 gene)
14 63a 25-Mar-08 M 3 OK OK C r 16 Cr16 no - - - -
15 8 1-Nov-2006 D0 OK OK A bc 2 Ac2/Ab2 OK B c 3 Bc3 mixed infection In een of beide samples een mixed infection;
16 8a 11-Jan-07 M 2 OK OK A c 2 Ac2 OK BA cb 32 Bc3/Ab2 same mix zelfde genotype wel in beide samples
17 14 10-Nov-2006 D0 OK OK C q 16 Cq16 OK BC ci 39 Bc3/Ci9 mixed infection 8, 14, 52
18 14a 15-Feb-07 M 3 OK OK C q 16 Cq16 OK C i 9 Ci9 M3 = 1 van de 2 van D0
19 52 27-Sep-2007 D0 OK OK A bc 2 Ab2/Ac2 OK B c 3 Bc3 mixed infection MSP-1F2
20 52a 3-Nov-07 M 1 OK OK A b 2 Ab2 OK B c 3 Bc3 M1 = 1 van de 2 van D0
21 36 12-Apr-2007 D0 OK OK C w 20 Cw20 OK C g 7 Cg7 D0 ≠ M2
22 36a 27-Jun-07 M 2 OK OK C v 19 Cv19 OK C g 7 Cg7 [one gene MSP1-F2]
23 17 20-Nov-2006 D0 OK OK C r 16 Cr16 OK C i 9 Ci9 D0 ≠ M2
24 17a 29-Jan-07 M 2 OK OK C s 15 Cs15 OK C k 10 Ck10 [both genes] Possible RE INFECTION
25 21 19-Dec-2006 D0 OK OK C t 17 Ct17 OK B d 4 Bd4 D0 ≠ M6 Verschillend genotype
26 21a 7-Jun-07 M 6 OK OK C s 15 Cs15 OK B e 5 Be5 [both genes] 17, 21, 22, 35, 36 , 60
27 35 11-Apr-2007 D0 OK OK C s 17 Cs17 OK C h 8 Ch8 D0 ≠ M2
28 35a 4-Jul-07 M 2 OK OK C x 21 Cx21 OK A b 2 Ab2 [both genes]
29 22 3-Jan-2007 D0 OK OK A b 2 Ab2 OK B c 3 Bc3 D0 ≠ M11
30 22a 18-Dec-2007 M 11 OK OK A b 17 Ab17 OK B d 4 Bd4 [both genes]
31 60 21-Nov-07 D0 OK OK AC bt 2 Ab2/Ct OK A b 2 Ab2 D0 ≠ M1
32 60a 4-Jan-2008 M 1 OK OK C w 17 Cw17 OK C l 11 Cl11 [both genes]/evt mix
33 16 17-Nov-2006 D0 OK no - - - - no - - - -
34 16a 6-Jun-07 M 7 OK OK AC t+ 18 At18/C OK A b 2 Ab2 GEEN UITSPRAAK
34
MWI RESULTS P. VIVAX RECRUDESCENCE PPQ TRIAL [aug 2008]
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CharacteristicGroup 1
(14 days)
Group 2
(7days)
Total
No. relapses 4 13 17
same/mixed genotype 3 (75%) 6 (46.2%) 9 (52.9%)
different genotype 0 (0%) 5 (38.5%) 5 (29.4%)
data missing/insufficient 1 (25%) 2 (15.4%) 3 (17.6%)
p = 0.26 when comparing same/mixed genotype to different genotype of both groups using Fisher’s exact test
Genotyping results
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Conclusions/Discussion
PQ 0.5mg/kg/day for 7 days is inferior to standard regimen (0.25mg/kg/day for 14 days) of PQ therapy in Suriname
In this study genotyping did not supply extra evidence for the inferiority of the 7 day regimen.
The study would be more convincing in an area where reinfection could be excluded (infections from same geographical area!).
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Questions?