A systematic review of CQ-resistant Plasmodium vivax malaria infections in India

Figures & data

Figure 1. PRISMA chart showing the inclusion of studies where CQ resistance was evaluated.

Wrong population – non P. vivax studies, non human studies, and the studies conducted outside india; Wrong study type – review article, letter to editors, case reports, conference abstracts.

Table 1. Classification of treatment failures in-vivo efficacy studies.

Author (year)	Whether WHO resistance criteria were followed (yes/no)	Definition of drug resistance criteria
Singh R.K et al. [11]	No	Inability to clear parasitemia within 7 days or the recurrence of parasitemia within 28 days
Nandy A et al. [12]	Yes	WHO’s ‘extended field test’ to determine the CQ sensitivity [13]
Srivastava H.C. et al. [14]	Yes	WHO standard definitions − 2002, 2003 [15,16]
Valecha N et al. [17]	No	Clinical deterioration, requiring hospitalization between Day 1 and 7 Presence of Parasitaemia with Axillary temperature - ≥37.5° between days 3 and 6 OR Presence of Parasitaemia between days 7 and 28
Mishra N et al. [18]	Yes	WHO standard definitions − 2009 [10]
Ganguly S et al. [19]	No	WHO standard definitions − 2009 [10]
Shalini S et al. [20]	Yes	WHO standard definitions − 2009 [10]
Rishikesh et al. [21]	No	WHO standard definitions − 2009 [10]
Valecha N et al. [22]	No	Presence of Parasitaemia on day 3 with fever Cure rate on day 28, parasite clearance time, and fever clearance time
Saravu K et al. [23]	No	WHO standard definitions − 2009 [10]

Table 2. Classification of drug resistance criteria for in-vitro studies.

Study	Assay used	Resistance Criteria
Matlani M et al. [24]	Schizont maturation assay	>100 nM IC50 values are considered as CQ resistant
Singh G et al. [25]	Schizont maturation assay	Schizont maturation at 8 pmol (CQ concentrations)/well
Shalini S et al. [20]	Schizont maturation assay	>100 nM IC50 values are considered as CQ resistant

IC₅₀ − 50% inhibitory concentration

Figure 2. Location of the included study sites (except the study conducted by Mishra N et al.).

Figure 3. Flow chart of the patient enrollment and follow-up in CQ drug efficacy studies.

LFU – lost to follow-up; ETF – early treatment failure; LCF – late clinical failure; LPF – late parasitological failure.

Table 3. Methodological characteristics of included studies.

Author (reference)	Year	Study design	Location of the study	Number of participants	Age group	Presence of a control group	Randomization	Dose of CQ	Dosage of PQ	Day of PQ Initiation
In-vivo efficacy studies
Singh R.K. et al. [11]	2000	Prospective cohort study	Bihar	75	14–70	No	No	1500 mg over 3 days	15 mg/day for 14 days	After 3 days
Nandy A et al. [12]	2003	Prospective cohort study	Kolkata, West Bengal, Mayurbhanj, Odissa	800	All age groups	No	No	25 mg/kg	Unclear	NA
Srivastava HC et al. [14]	2003–2005	Prospective cohort study	Deva and Pansora, Anand District, Gujarat	138	All age groups	No	No	Adults: 1500 mg base or Children: 25 mg/kg base	0.25 mg/kg for 5 days	Day 28
Valecha N et al. [17]	2006	Open, prospective trial	Chennai, Gautam Budh Nagar, Navi Mumbai	287	≥6 months	No	No	Adults: 1500 mg over 3 days Children 25 mg/kg base over 3 days	Unclear	NA
Mishra N et al. [18]	2009–2010	Prospective cohort study	Multicentric (25 sentinel sites)	210	All age groups	No	No	25 mg/kg	0.25 mg/kg for 14 days	Day 28
Ganguly S et al. [19]	2011	Open-label, interventional trial	Kolkata	125	≥5 years	No	Yes	25 mg/kg	0.25 mg/kg for 14 days	Day 0
				125				25 mg/kg	NA	NA
Shalini S et al. [20]	2014	Prospective cohort study	Chennai	125	10–70	No	No	1500 mg	0.25 mg/kg body weight daily for 14 days	Day 28
Rishikesh et al. [21]	2016	Prospective cohort study	Manipal	125	≥18 years	No	No	25 mg/kg body weight over 3 days	0.25 mg/kg body weight daily for 14 days	After 3 days
Valecha N et al. [22]	2016	Open label, multicentric trial	New Delhi, Kolkata, Vadodara, Mumbai, Visakhapatnam, Mangalore, and Bikaner	158	13–65	No	No	2500 mg over 3 days	15 mg/kg over 14 days	After 3 days
Saravu K et al. [23]	2016	Prospective cohort study	Manipal	161	≥18 years	No	No	25 mg/kg body weight over 3 days	(0.25 mg/kg body weight daily for 14 days	Day 0
In vitro drug efficacy studies
Singh G et al. [24]	2014	Cross-sectional	Mumbai	22	4–65	NA	NA	NA	NA	NA
Matlani M et al. [25]	2020	Cross-sectional	Delhi	23	Unclear	NA	NA	NA	NA	NA
Shalini S et al. [20]	2014	Prospective cohort study	Chennai	96	10–70	NA	NA	NA	NA	NA

Table 4. Summary of CQ treatment failures in Plasmodium vivax malaria infections in India.

Author (reference)	Total no. of patients enrolled	Days of follow-up	No. of patients completed the follow-up	Clinical Treatment Failure			Microbiological Treatment Failure n (%)	Total no CQR or TF n (%)
				ETF	LCF	LPF
In vivo efficacy studies
R.K. Singh et al. [11]	75	28	75	0	5 (6.67%)	12 (16%)	NA	17 (22.66%)
Nandy A et al [12]	800	28	480	0	0	0	NA	0
Srivastava HC et al. [14]	138	28	122	0	0	6 (4.92%)	NA	6 (4.92%)
Valecha N et al. [17]	287	28	233	0	0	0	NA	0
Mishra N et al. [18]	210	28	185	0	0	0	NA	0
Ganguly S et al. [19]	250	42	205	0	1 (0.49%)	0	NA	1 (0.49%)
Shalini S et al. [20]	125	28	107	0	0	0	NA	0
Rishikesh et al. [21]	125	28	122	1 (0.82%)	0	0	NA	1 (0.82%)
Valecha N et al. [22]	158	42	104	0	0	0	NA	0
Saravu K et al. [23]	161	28	154	0	0	0	NA	0
Total	2329	NA	1787	1 (0.06%)	6 (0.33%)	18 (1.01%)	NA	25 (1.39%)
In-vitro/ex vivo studies
Singh G et al. [24]	22	NA	22	NA	NA	NA	5 (22.73%)	5(22.73%)
Matlani M et al. [25]	23	NA	23	NA	NA	NA	6 (26.09%)	6 (26.09%)
Shalini S et al. [20]	96	NA	96	NA	NA	NA	0	0
Total	141	NA	141	NA	NA	NA	11 (7.80%)	11 (7.80%)

ETF: early treatment failure; LCF: late clinical failure; LPF: late parasitological failure; TF: treatment failure; NA: not applicable.

Figure 4. Risk of bias assessment by JBI’s critical appraisal checklist.

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