A field-hut in Kong Chro district, Gia Lai province

Huynh Hong Quang et al.,

Institute of Malariology, Parasitology and Entomology Quy Nhon

Abstract

Introduction: Primaquine, an 8-aminoquinoline drug capable of clearing the intra-hepatic schizonts, hypnozoites of Plasmodium vivax, and holds a unique and unreplaceable radical cure, but the non-compliance with 14 day-course primaquine regimen is a big problem now. Methods: A study carried out with patients' record-based retrospective and prospective study design o­n vivax patients. Results: In the retrospective, the malaria treatment for falciparum and vivax malaria with blood asexual forms is right, but doctors filled prescription of falciparum gametocytes and vivax hypnozoites are not enough 20% (for P. falciparum malaria) and 22.2% (for P. vivax malaria) in patients' case records at hospitals. And in prospective study, primaquine regimen fully compliance was low 26.7% (4/15 cases) and non-compliance with full primaquine dose was 73.7% (11/15 cases) by self-administrative therapy. Conclusions: the patients with non-compliance can have an impact o­n the vivax malaria transmission dynamics and relapses. Hence, how to guide the malaria patients in order to improve compliance with the treatment prescribed, and furthermore, need to be replacement of primaquine with newer drugs, tafenoquine for example.

Keywords: Plasmodium vivax, primaquine compliance.

1. BACKGROUND

Plasmodium vivax causes important morbidity and poses multiple challenges for malaria elimination. It has the widest geographical distribution of the five human Plasmodium spp. parasites with about 35% of the world's population being at risk [5]. In Vietnam, particularly in recent 3 years, in areas where both species coexist, the incidence of P. vivax appears to decrease more slowly than that of P. falciparum. Thus, the proportion of P. vivax cases increases as the incidence of malaria is reduced. Particularly, P. vivax has a dormant hypnozoite stage that can cause multiple relapses after a primary infection [2], but is undetectable with current diagnostic methods.

According to latest National guidelines for malaria treatment in Vietnam (2013) and WHO guidelines for malaria treatment (2015) involved in full 14-day course of PQ [1],[5], but at some health facilities from provincial to communal level, several physicians still incorrectly prescribe PQ, and they do not know whether or not patient?s compliance with full regimen of PQ. These issues led to intermittent relapse attack, chronic infection, wide spread out in community, and vivax malaria elimination roadmap will be a challenge. In order to understanding of this status, this study conducted with the following objectives:

1. To evaluate the prescribe pattern of health staffs at health facilities in selected provinces of primaquine (PQ) according to the MoH's National guidelines;

2. To evaluate the PQ drug regimen compliance from patients in using fully 14 day-course of PQ.

2. METHODS

2.1.Study designs

-Retrospective and cross-sectional design to calculate the above indicators, percentage, numbers at each and total in 3 selected provinces (Gia Lai, Dak Lak, and Ninh Thuan province);

-Prospective study design to evaluate of PQ 14 day-course regimen compliance from vivax malaria patients in 3 above pilot provinces where high proportion of vivax malaria cases.

2.2.Sample size

-Withretrospective study: All malaria patient's case records (PCRs) from provinces/ districts hospital and communes health facilities in whole year 2015 and first 3 months of year 2016;

-With prospective study: at least 30 vivax malaria cases per provinces of Gia Lai, Dak Lak, and Ninh Thuan (here is estimated minimum sample size of 10 cases per communal health unit.

2.3. Timeframes

From June to December 2016.

-With retrospective study: Selected in each province, 1 provincial general hospital, and private hospital, 2 districts hospitals and 4 communal health stations (belonging to above 2 districts):

+ Gia Lai province (provincial hospital, 2 district hospitals of Krong Pa and Kong Chro, 4 communes of Ia Drech and Dat Bang belonging to Krong Pa, So Ro and Dak Pling belonging to Kong Chro);

+ Dak Lak province (provincial hospital, Thien Hanh general hospital, 2 district hospitals of Ea Sup and Ea Hleo, 4 communes of Cu Kbang and Ea Le belonging to Ea sup, Ea Hleo and Ea sol belonging to Ea Hleo);

+ Ninh Thuan province (provincial hospital, 2 district hospitals of Ninh Son and Thuan Bac, 4 communes of Hoa Son and Lam Son belonging to Ninh Son, Phuoc Chien and Phuoc Khang belonging to Thuan Bac);

-With Prospective study

In each province: selected 1 districts and 3 belonging communal health stations (CHSs):

+ In Gia Lai: Krong Pa district and 3 CHSs (Ia Drech, Ia Mlah, Dat Bang);

+ In Dak Lak: Ea Sup district and 3 CHSs (Cu K?bang, Ea Sup, and Ea Le);

+ In Ninh Thuan: Thuan Bac district and 3 CHSs (Phuoc Chien, Cong Hai, Phuoc Khang).

2.4. Indicators

-No. of confirmed malaria patients from case records;

-No. of confirmed malaria patients have discharged officially/unofficially from hospitals;

-No. of P. vivax malaria PCRs were standard or substandard treated in line with PQ 14-day course regimen in each survey sites;

-No. of P. falciparum malaria PCRs were standard or substandard treated with 1-day PQ regimen followed by ACTs;

-Amount of PQ in previous year was supplied by NMCP (continuously or intermittent providing), and reasons for lack of PQ in health facilities, if any stock outs;

-No. of P. vivax/ P. falciparum malaria patients who using complete PQ regimen and uncomplete PQ regimen at their home;

-The reasons why they do not use full course of PQ (lost drug, forgot to take drug, needless to taken as stopped symptoms, fair to side-effects from drugs);

-Number, percentage of vivax malaria cases were not compliance with national guidelines.

2.5. Monitoring, Evaluation and Follow-up

To ensure that this survey of prescribe pattern and patients compliance in line with PQ treatment regimen whether running well and effectively:

-Conduct this activity protocol after approval was obtained;

-Review all vivax malaria patients case records (PCRs) in hospitals lines (including of PCRs of monoinfection, or PCRs of mix-infection with P. vivax);

-After all PCRs investigation in health facilities, IMPE principle investigator should be meeting together with all doctors, pharmacists, technicians of hospitals for conclusion;

-In prospective study, if not PQ compliance, asking by questionnaire to list the reasons why (open-ended and closed-ended questionnaire to P. vivax malaria patients).

2.6. Data analysis

3. RESULTS

All of the result?s data obtained from this activity (including retrospective and prospective study design) were used as reference for the objectives above of the National strategy for malaria control and elimination roadmap in Central provinces and Vietnam in general, especially in vivax malaria elimination from now to 2030.

3.1. Investigated malaria case record and prescription patterns in retrospective study

Table 1. Total of investigated malaria cases in all health facilities in 3 selected provinces

           All communal health stations (CHS) are not belonging to TES sentinel sites

           Total of 341 investigated patients? case records (PCRs) in 3 selected provinces. Proportion of confirmed cases is 86.8% and the rest of clinical cases (13.2%). o­n the parasite structure, in Gia Lai and Dak Lak relative equal in P. falciparum and P. vivax, but in Ninh Thuan, P. falciparum (72.1%) is much more than P. vivax (27.9%).

Table 2. Malaria case diagnosis by gold standard and/ or rapid diagnostic tests (RDTs)

          Most of malaria cases were diagnosed by giemsa slide (100%), none of cases used o­nly RDTs for diagnosis. Proportion of malaria cases used both giemsa slide and RDTs at the same time are 60.7%, 28.6%, and 31.4% in Gia Lai, Dak Lak, and Ninh Thuan respectively.

Table 3. Malaria cases in Gia Lai province from 2015 to first 4 months 2016

        Number of malaria cases in Krong Pa hospital, P. vivax is more than P. falciparum.

Table 4.Malaria cases in Dak Lak province from 2015 to first 4 months 2016.

       In malarial parasite structure in Dak Lak showed that P. vivax is more than P. falciparum.

Table 5. Malaria cases in Ninh Thuan province from 2015 to first 4 months 2016

The study of malarial parasite structure in selected sites in Ninh Thuan province showed that P. vivax is less than P. falciparum in formula.

Table 6. Malaria diagnosis and treatment in rational of National guidelines in Gia Lai province

          Involving in clinical malaria cases diagnosed by provincial hospital in Gia Lai 8/8 (100%) and 1/1 (100%) case from Kong Chro hospital are unappropriated.

Table 7. Malaria diagnosis and treatment in rational of National guidelines in Dak Lak province

The clinical malaria diagnosis are unappropriated 87.7% and 70% of case in Dak Lak general hospital and Thien Hanh general hospital, respectively. In the malaria treatment for falciparum and vivax malaria with blood asexual forms is right, but doctors filled prescription of gametocytes and hypnozoites are not enough 20% (for P. falciparum) and 22.2% (for P. vivax).

Table 8. Malaria diagnosis and treatment in rational of National guidelines in Ninh Thuan province

In Ninh Thuan general hospital, the clinical malaria diagnosis are very high and inappropriate with 7/7 (100%), and in the malaria treatment for falciparum and vivax malaria with blood asexual forms is right, but doctors filled prescription of gametocyte is not enough (27.3%).

Table 9. Supplying of PQ by Provincial Center of Malariology, Parasitology, and Entomology

         Concerning to available PQ medicines in houseware in provincial center of malariology, parasitology, and entomology (CMPE) and IMPE Quy Nhon for supplying to all treatment facilities, the results showed that PQ is always available.

3.2. Primaquine 14 day-course regimen compliance from vivax malaria patients

Table 10. Malaria patients situation in 3 selected provinces

         All of confirmed vivax malaria case in these provinces were used to apply self-administration therapy (SAT) with chloroquine (3 consecutive days) plus primaquine (14 consecutive days) regimen at their home. Health staff of the CHSs will be responsible to follow up or directly observed and asking (DOA) or cellphone in case of patient far away from their home about the PQ regimen compliance.

Table 11. The PQ regimen compliance from vivax malaria patients in Gia Lai provinces

         Follow up patients who taking 14 day-course of PQ: In Gia Lai: o­nly 2/6 cases fully used, and 4/6 cases used under 7 days and stop using (in Ia Mlah), and 2/2 cases used under 7 days (in Ia Drech). In Dak Lak: only 1/4 and 1/1 cases fully used in Cu Kbang and Ea Sup CHS, there is 3/4 cases in Cu Kbang used under 7 days and stop using later. In Ninh Thuan: none of cases fully used in Phuoc Chien and 1/1 case in Phuoc Khang used under 7 days and stop using later.

4. DISCUSSION

4.1. Investigated malaria case record and prescription patterns in retrospective study

        Total of 341 investigated patients' case records (PCRs) in 3 selected provinces, in which 145 cases from Gia Lai province, 126 cases from Dak Lak, and 70 cases from Ninh Thuan. Proportion of confirmed cases is 86.8% and the rest of clinical cases (13.2%). Concerning o­n parasite formula, in Gia Lai and Dak Lak were relative equal in P. falciparum and P. vivax, but in Ninh Thuan, P. falciparum is higher than P. vivax (72.1% vs. 27.9%), and P. malariae is very low. Most of malaria cases from 3 provinces were diagnosed by giemsa staining slide as gold standard (100%), none of cases used o­nly RDTs for diagnosis. Proportion of malaria cases used both giemsa slide and RDTs in diagnosis at the same time are 60.7%; 28.6% and 31.4% in Gia Lai, Dak Lak, and Ninh Thuan province respectively. This is suitable for cover all malaria case in community, particular in case of undetectable microscopy threshold [3],[6].

         Compared to the previous year, number of malaria cases in Gia Lai general hospital, Kong Chro and Krong Pa hospitals were reduced sharply. Especially, in Krong Pa hospital, P. vivax is more than P. falciparum in formula. In malarial parasite structure in selected sites in Dak Lak showed that P. vivax is more than P. falciparum in formula. In malarial parasite structure in selected sites in Ninh Thuan province showed that P. vivax is less than P. falciparum in formula. Involving in clinical malaria cases diagnosed by provincial hospital in Gia Lai, 8/8 (100%) and 1/1 (100%) case from Kong Chro hospital are unappropriated due to reasons: (i) giemsa slide o­nly taken o­ne time before; (ii) not applied specific Pf/Pv RDTs for help to exclude malaria diagnosis. And in the malaria treatment for falciparum and vivax malaria with blood asexual forms is right, but doctors filled prescription of falciparum gametocytes and vivax hypnozoites are not enough (4.35% for P. falciparum and 17.4% for P. vivax missing PQ).

Similarity in Gia Lai, concerning o­n clinical malaria diagnosis are unappropriated of 87.7% and 70% of case in Dak Lak general hospital and Thien Hanh general hospital, respectively. The reasons why so high in clinical malaria? Because of many reasons such as (i) taken blood for giemsa slide o­nly o­ne time, this was not enough for cover whole life-cycle of Plasmodium spp.; (ii) not applied specific Pf/Pv RDTs for help to exclude malaria. And in the malaria treatment for falciparum and vivax malaria with blood asexual forms is right, but doctors filled prescription of falciparum gametocytes and vivax hypnozoites are not enough (20% for P. falciparum malaria and 22.2% for P. vivax malaria in line with national guideline) in patients? case records at hospitals. Alike with above provinces, o­n clinical malaria diagnosis in Ninh Thuan general hospital were very high and inappropriate with 7/7 (100%) and similar reasons, and the malaria treatment for falciparum and vivax malaria by blood schizonticidal drugs was right, but doctors filled prescription of falciparum gametocyte is not enough 27.3% in patients.

          In order to investigate whether or not available PQ medicines in warehouses in all provincial center of Malariology, Parasitology, and Entomology (CMPE) and Institute of Malariology, Parasitology, and Entomology (IMPE) Quy Nhon for supplying to all treatment facility levels in long-term, the results showed that from April 2014 to April 2016, the kind of PQ 13,2mg (7,5mg base) is always available. This different to pre-April.2014, due to interchange between P. falciparum and P. vivax in formula in most of Central highland provinces of Vietnam, especially in malaria endemic zones with predominant of P. vivax, hence lack of PQ source in time. Except Dak Lak provincial general hospital anticipate of PQ medicines ?some yes, some no? (Yes/No) in 2014.

4.2. Primaquine 14 day-course regimen compliance from vivax malaria patients

           In order to access to PQ regimen compliance from patients who get vivax malaria, this pilot study was conductedat Krong Pa district hospital and belonging 3 CHSs of Ia Drech, Ia Mlah, and Dat Bang (in Gia Lai province), at Ea Sup district hospital and belonging 3 CHSs of Cu Kbang, Easup, and Ea Le (in Dak Lak province), and at Thuan Bac district hospital and 3 belonging CHSs of Phuoc Chien, Cong Hai, and Phuoc Khang (in Ninh Thuan province). Here were 3 selected CHSs with the highest number of vivax malaria cases in the year of 2015.

         All of confirmed vivax malaria case in these provinces were used to apply self-administration therapy (SAT) with chloroquine (3 consecutive days) plus primaquine (14 consecutive days) regimen at their home. Health staff of the CHSs have responsible to followed up or directly observed and asking (DOA) or cellphone contacted in case of patients far away from their home about the PQ regimen compliance.In total 29 confirmed malaria cases in this prospective study, all of P. falciparum, P. vivax and P. malariae cases aged 15 or above, and gender of male to female ratio is 27/2.

        Follow up after treatment of chloroquine plus primaquine (PQ) for 8 confirmed vivax malaria patients in 3 communes in Gia Lai, health staff indicated for patients more 14 day-course of PQ. The data showed that o­nly 2/6 cases fully used of PQ, and 4/6 cases used PQ under 7 days and stop using after clinical symptom withdraw (in Ia Mlah), and 2/2 cases used under 7 days (in Ia Drech). In Dak Lak, follow up after treatment of PQ for 5 confirmed vivax malaria patients, health staffs indicated for patients more 14 day-course of PQ. The data showed that o­nly 1/4 and 1/1 cases fully used in Cu Kbang and Ea Sup, respectively. There were 3/4 cases in Cu Kbang used under 7 days and stopped using later. In Ninh Thuan, follow up after treatment of PQ for 2 confirmed vivax malaria patients, health staff indicated for patients more 14 day-course of PQ, but the data showed that there were no cases fully used in Phuoc Chien and 1/1 case in Phuoc Khang used under 7 days and stop using later. These data showed that a presumed problem of poor compliance with PQ regimen, may be overcome by simple health messages even when the majority of individuals are illiterate and without formal education. Unsupervised treatment with 14-day PQ when combined with simple instruction can avert a significant amount of the morbidity associated with relapse in populations, and prevent to chronic infestation in community [7].

CONCLUSIONS

With above results, this activity enables national malaria control programme Vietnam to implement evidence-based malaria strategic plans, with focus o­n effective coverage of diagnosis and treatment by latest national guideline malaria diagnosis and treatment. Particularly, how to encourage all malaria patients use rational antimalaria medicines (including asexual form and sexual drugs of PQ) by health-care providers, especially in P. vivax malaria cases need to be used long course PQ. If malaria patients do not use PQ in , most of Plasmodium spp. gametocyte and hypnozoite forms shall not clear in patients [6]. These mean continuously transmit in communities, and relapse, and chronic infestation. Due to PQ compliance weakness, finding new candidates for primaquine replacement is needed.

Conflict of interest

The authors have no other conflicts of interest.

Acknowledgement

This study consumed huge amount of work, research and dedication. Still, implementation would not have been possible if we did not have a support of many individuals and organizations. Therefore, we would like to extend our sincere gratitude to all of them, especially, we are thankful for WHO?s financial and logistical support and for providing necessary guidance concerning activity implementation, and Dr. Tran Cong Dai of expertise, and technical support.

REFERENCES

1.Ministry of Health Vietnam (2013). National guidelines for malaria diagnosis and treatment.

2.WanchaiManeeboonyang, SaranathLawpoolsri et al., (2011). Directly observed therapy with primaquine to reduce the recurrence rate of Plasmodium vivax infection along the Thai-Myanmar border. Southeast Asian J Trop Med Public Health, Vol 42 No. 1 January 2011.

3.Leslie T, Rab MA, Ahmadzai H, Durrani N et al., (2004). Compliance with 14-day primaquine therapy for radical cure of vivax malaria: A randomized placebo-controlled trial comparing unsupervised with supervised treatment. Trans R Soc Trop Med Hyg.2004;98(3):168-73.

4.Deepika Fernando, Chaturaka Rodrigo, Senaka Rajapakse et al., (2011). Primaquine in vivax malaria: An update and review o­n management issues.Malaria Journal2011, 10:351

5.WHO (2015). Malaria treatment guidelines, Third edition.

6.WHO (2015). Control and Elimination of Plasmodium vivax malaria - A technical brief

7.WHO (2015). Confronting of Plasmodium vivax malaria.

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