Influence of blister packaging on the efficacy of artesunate + mefloquine over artesunate alone in community-based treatment of non-severe falciparum malaria in Myanmar.

Influence of blister packaging on the efficacy of artesunate + mefloquine over artesunate alone in community-based treatment of non- severe falciparum malaria in Myanmar Tin Shwe,1 Myint Lwin,2 & Soe Aung3 Three studies were carried out to determine the need, acceptability, and efficacy of adding mefloquine to artemisinin derivatives (AD) for the first-line treatment of uncomplicated falciparum malaria. The first was a retrospective study of 255 basic health workers which showed that their recommendation ofAD to patients depended on their level of training. None of the paramedics/midwives and only 9% of 129 doctors had prescribed AD, and no one had recommended AD in combination with mefloquine; 72% of patients used courses that were too short for parasitological cure. To promote the addition of mefloquine to AD regimens we conducted intervention workshops with health care providers and subsidized the cost of mefloquine to patients. In the second study, we interviewed200 patients before and after the intervention to evaluate drug compliance with fulidoses ofAD and use ofsubsidized mefloquine. After the intervention, we found that only 3.6% had used mefloquine and 62% had taken non-curative doses of AD. In the third study, we provided blisterpacks of medication in daily doses and compared the intake ofAD + placebo (158 patients) with that ofAD + mefloquine (222 patients) for 5 days. The compliance with both regimens was 99%. Blood smears for parasites on day 28 showed one positive in the AD + mefloquine group and 7 positive in the AD group. We conclude that provision of blisterpacks of daily doses is a very effective way to improve compliance with short courses and drug combinations, but the efficacy of the combination in Myanmar in this particular study was only marginally higher than that of AD alone. Introduction Artemisinin derivatives (AD, i.e. artemether injec- tions, artesunate injections, and artesunate tablets) have been shown to be effective in the treatment of severe Plasmodium falciparum malaria in south- east Asia. Unfortunately, these compounds have a high recrudescence rate (up to 25-40%) even when used for the recommended 5 days to treat uncompli- cated malaria cases. Although these compounds have recently become widely available in Myanmar, prescribing practices of health workers and the com- pliance of patients with uncomplicated malaria have not been studied. This information is needed to de- velop strategies for the control and rational use of these drugs in order to preserve their effectiveness in I Research Scientist and Head, Clinical Research Unit, Depart- ment of Medical Research (DMR), Ministry of Health, Dagon PO, Yangon, Myanmar. 2 Director of Research, DMR, Ministry of Health, Yangon. Myanmar. 3 Deputy Director, Vector-borne Diseases Control, Ministry of Heafth, Yangon, Myanmar. Requests for reprints should be sent to Dr M. Gomes at the address shown on p. 9. Reprint No. 5849 treating severe and complicated falciparum cases, especially in areas of multidrug-resistant malaria. In 1994 a hospital-based study in Myanmar showed that a 7-day treatment using oral dihydro- artemisin1n (Cotecxin) was 100% efficacious against nonsevere malaria (1); there was no recrudescence in any of the 30 patients who were followed up for 28 days. As for compliance, another study of 20 outpa- tients with non-severe malaria showed that 25% dis- continued when the symptoms cleared and did not finish the full course (2, 3). It was considered unrea- sonable to expect 7 days of compliance, and when 3- and 5-day regimens were examined the cure rates fell to 84% and 89.5%, respectively. Resistance to mefloquine, the third-line drug in most of Myanmar, has been documented in many areas of South-East Asia. Along the Thai-Myanmar border, for exam- ple, 41.7% of patients have been reported to be re- sistant to mefloquine in vivo (4). However, there is no reported resistance to the combination artesunate and mefloquine (5-7). We therefore considered pro- moting the addition of mefloquine to artesunate regimens in order to decrease the probability of re- crudescence and retard the spread of mefloquine re- sistance (8-11). The following studies were conducted in sequence: Bulletin of the Word Health Organization, 1998, 76 (Suppl. 1): 35-41 0 Word Health Organizaton 1998 35 Tin Shwe t al. 1. Use ofartemisinin. a retrospective study to char- acterize current use and conditions for the use of artemisinin derivatives. 2. Subsidized mefloquine intervention: to promote the use of a combined artesunate + mefloquine regi- men for uncomplicated malaria by educating health care providers and subsidizing the cost of mefloquine to patients. 3. Packaging intervention: to improve the compli- ance with artesunate + mefloquine by packaging and distributing them together in blister packs. Use of artemisinins Methods This retrospective study to evaluate current use of artemisiin compounds in Myanmar was conducted in the following areas: - two townships with a high prevalence of malaria (Pyin Oo Lwin and Myit Kyi Na); - one township where drug resistance is common (Mawlamine); - one township in central Myanmar (Thayarwady); - one township with a low prevalence of malaria (Maubin); and - one township with a large migrant population close to jade mines (Moekaung). Questionnaires on the use of artemisinins were prepared for interviews with the following individu- als: hospital doctors and general practitioners in the townships; nurses, health assistants and midwives; auxiliary midwives and voluntary health workers; drug store owners in the townships; and former hos- pital patients who had experienced severe and com- plicated malaria. Meetings with the hospital doctors and general practitioners were held through the vari- ous branches of the Myanmar Medical Association, at which the questionnaires were distributed and filled in by the doctors. A similar exercise was re- peated with the nurses and paramedical workers in the townships. A coverage of approximately 80% of all doctors and nurses from the specified townships was obtained. Results A total of 129 doctors were interviewed. Artemisinin compounds were prescribed as first-line treatment by 9.1% for uncomplicated malaria, 37.6% for ma- lana with complications, 33% for drug-resistant ma- laria, and 11.9% for reasons not directly related to malaria (e.g. requested by the patient). Most doctors did not prescribe full courses, mainly because of the cost of the drug. Artemisinin derivatives alone were felt to be effective and the doctors considered they had no reason to add mefloquine to prevent recru- descence. Many doctors indicated that they did not know the dose and toxicity of the drugs (28.9%) or have information on their clinical efficacy (16.5%). A total of 255 basic health workers were inter- viewed. Approximately 50.6% were aware of artemisinin derivatives and 20% had used them in treatment, with 27.5% of such use being for patients with uncomplicated malaria. Paramedical health workers, auxiliary midwives and voluntary health workers all prescribed chloroquine, sulfadoxine-pyrimethamine, and qui- nine for malaria treatment. The majority of drug store owners (71 were interviewed) stocked artemether injections, 38% stocked artesunate injec- tions,. and 78.9% stocked oral artesunate tablets. Artemether injections were sold at the average price of 605.6 kyats per box of eight ampoules (US$ 1 = 600 kyats). Artesunate blister strips were sold at an average price of 129 kyats each (US$ 0.20). Artemether was also sold as single ampoules in 95.8% of shops, and 71.8% of purchases were by relatives of patients. Hospital patients with severe and complicated malaria were mostly treated with quinine injections, but a significant number (22.6%) were treated with artemether injections. One-fifth of all patients used artesunate tablets following discharge. Discussion The total number of patients treated by the doctors interviewed during the study was 9000-10000 per month, about one in every ten of whom received artemisinin compounds. The majority prescribed doses that would not prevent recrudescence, i.e. short regimens and without mefloquine. Subsidized metloquine intervention Methods The objective of this intervention was to subsidize mefloquine pnces in the hope that this would en- courage its addition to short courses of artesunate for treatment of uncomplicated falciparum malaria. This combined regimen was promoted through workshops for doctors (public and private practition- ers) and basic health workers. A questionnaire was WHO BtAltin OMS. Vol 76 (Suppl. 1) 199836 Efficacy of artesunate + mefloquine In Myanmar devised to assess their knowledge of treatment with the artemisinin derivatives, after which they were provided with verbal and written information on the treatment of uncomplicated malaria with artemisinin and mefloquine. Mefloquine tablets were subsidized through vouchers for patients and made available in the hos- pital and government clinics and rural health centres to doctors and basic health workers. The latter were asked to inform each patient who was prescribed oral artemisiin preparations to take these drugs with mefloquine, which would be available on pre- sentation of the voucher at the subsidized price at the specified outlets. Both before and after the intervention, a random cohort of 200 patients (100 from a rural area and 100 from an urban area) who had sought advice from the workshop-trained doctors and basic health workers were followed up at home with the help of a health assistant to determine the drugs taken for treatment, the advice they received, and whether they used mefloquine. Results Before the intervention, 72% of all patients treated with the artemisinins had used less than the full regi- men, and never in combination with mefloquine. Of the 200 patients surveyed before the intervention, 10% had been treated by hospital doctors, 58% by general practitioners, and 4% by nurses while 28% had bought the artemisini derivatives over the counter. Of those patients who went to the doctors (in public or private practice), none had taken mefloquine. After the intervention, 1780 packets of artesunate and no mefloquine were sold through the non-subsidized outlets. Of those dealers who kept records, 20% of the artemisinins sold had been prescribed by doctors, 11% by basic health work- ers, 59% by traders and 10% by patients for self-treatment; 46% of those who bought the artemisinins were given a voucher for mefloquine to be redeemed at the specified outlets, but no one took up this option. Only in the case of the hospital pharmacy, where both artesunate and mefloquine were available, did 100% of the hospital patients buy the full course of artemisinin plus mefloquine; this group constituted 3.6% of the total sample of patients treated for malaria. Compli- ance with the full 5-day regimen of artesunate was 62%. The reasons given for not using mefloquine in combination with the artemisinin derivatives were inconvenience (owing to distance) of redeeming the voucher for mefloquine at the specified outlets, con- fidence in artesunate monotherapy, and lack of funds to purchase mefloquine even at the subsidized price. Through interviews with patients, we learned that cost was not a significant factor hindering the pur- chase of mefloquine; however, its non-availability at the same outlets that sold artesunate was a constraint against combined therapy. Discussion Our results indicate that special packaging for both artesunate and mefloquine would ensure that both drugs were always sold and taken together. This advantage to patients could more than make up for the higher expense (at the unsubsidized price of mefloquine) because of the convenience if one had to use combined treatment. Packaging intervention The objective of this study was to examine the effec- tiveness of a combined package (5-day course of artesunate + mefloquine) in increasing compliance to both drugs and in reducing the malaria recrudes- cence rate. The packaging of the 5-day course was con- sumer friendly and consisted of a large transparent packet with five transparent strips, each containing the daily dose, marked day 1 to day 5. The dose for the second day included either mefloquine or a placebo. An instruction leaflet in simple Burmese was included in the package explaining the regimen and the daily dose to be taken. A pre-intervention study assessed the willing- ness of dealers in Bago township to sell these packets of antimalarials and the patients' acceptance and un- derstanding of the packaging and instructions. This was followed by a larger double-blind study in six rural health centres, 160km from Yangon, to as- sess and compare the efficacy of 5-day regimens of oral artesunate + mefloquine and of artesunate alone in the community setting. In addition, the study assessed the patients' compliance rates using the new packets and compared them with those ob- tained previously (studies 1 and 2 above). Methods Six rural health centres (RHC) in a malaria-endemic area within 160km of Yangon were selected on the basis of their willingness to participate, and their capacity to complete the study. Each centre had 4-5 subcentres run by a midwife, each one serving 3-5 villages with 500-1000 inhabitants in each. All six WHO BEilbin OMS. Vol 76 (Supp4. 1)1998 37 Tin Shwe et al. Fig. 1. Example of.a blister pack for a 5-day course of artesunate. + mefloquine Including markers. Dy I Day2 Day3 Day4 Day5 I stuctions ARTESUNATE. ARTESUNATE ARTESUNATE ARTESUNATE ARTESUNATE MEFLOQUINE QUININE CHLOROQUINE *D 0 WHO 97536 centres had similar malaria transmission seasons and transmission patterns, as well as similar demographic and occupational features. The drug packets were prepared, with daily dos- ages, as follows (Fig. 1): - day 1: 4 tablets artesunate; - day 2: 2 tablets artesunate and 3 tablets of mefloquine (intervention group) or paracetamol (control group); - day 3: 2 tablets artesunate and one tablet of qui- nine (as a marker of compliance); - day 4: 2 tablets artesunate; and - day 5: 2 tablets artesunate and one tablet of chlioroquine (as a marker of compliance). Compliance on days 3 and 5 was measured through a urine sample taken on day 7. The blister packets were sold at the six health centres. The Intagaw and Gyogone RHCs (interven- tion group) received the blister packs containing artesunate and mefloquine, while the other four RHCs (control group) received artesunate with paracetamol as the placebo. The paracetamol and mefloquine tablets were indistinguishable, and the health centres were not told which group they were in. Drugs were sold at full price, with no difference in price between the placebo and combined drug packets. The criteria for inclusion in the study (both intervention and control groups) were patients aged >12 years who attended the RHC's outpatient clinic, who had a slide-confirmed (nonsevere) P. falciparum infection, and who had taken no anti- malarial medication during the previous 7 days. The study was explained to the eligible patients; those who consented to participate purchased the medica- tion (blister packs), the use of which was explained to each patient by the health assistant. A total of 60 private practitioners, 90 basic health staff, and 10 dealers from the two townships, where the six RHCs were located, were recruited to participate in the pre-intervention training. Each participant was given information verbally, and in booklets, on how to prescribe or sell the blister packs. The booklets (in English for the physicians and in Burmese for the dealers and local health staff) were distributed free. They were instructed to advise all patients to buy the entire blister pack and to take all the tablets; each pack contained instructions in simple Burmese on the importance of compliance with the full course. The number of sales was re- corded. At the end of the study, 300 blister packs were sold through the ten shops chosen by the town- ship medical officer. There were no adverse com- ments from either the drug sellers or malaria patients. All patients were informed that the treat- ment regimen was artesunate with or without mefloquine. WHO Bulletin OMS. Vol 76 (Suppl. 1) 199838 Efficacy of artesunate + mefloquine In Myanmar Table 1: Comparison of efficacy of artesunate + mefloquine against artesunate alone No. wfth positive smear on: No. of subjects No. +ve for No. at 28 Treatment and place screened P. fa/ciparum days Day 7 Day 28 Remarks Artesunate + mefloquine: Intagaw 329 205 205 2 1 P.f. 1 patient hospitalized (giddiness) 5 patients with some giddiness Gyogone 35 17 17 0 0 Subtotal 364 222 222 2 1 Artesunate + placebo: Phayagyi 243 165 115 0 7 P.f. 1 patient hospitalized (vomiting) Sarbutaung 44 22 14 0 0 Kyaunta 80 26 17 0 0 Pyinbonegyl 35 20 12 0 0 Subtotal 402 233 158 0 7 Total 766 455 380 2 8 Each Plasmodium falciparum slide-positive pa- tient who purchased the blister pack from the RHCs was followed up at home on day 7 and day 28 by the respective RHC health assistants, and the parasitological status was assessed on each day by blood smears. On day 7. patients were also inter- viewed regarding treatment compliance - i.e. completing the prescribed course - and asked to show any remaining tablets. Finally, a urine sample from each patient was taken for subsequent analysis of the presence of chloroquine (Lelijveld-Kortmann test) and quinine (Mayer-Tanret reagent test) (12). For the calculation of statistical power and sam- ple size, the mefloquine group was expected to have a 100% cure rate; the failure rates in the placebo group, which we considered useful to detect, was expected to be greater than 15%. The minimum sample size for each of the two groups (P = 0.95, power = 0.20) was calculated to be 60; total sample size was therefore 120. However, a much larger number were screened to make up for negative smears or P. vivax malaria and for loss to follow-up on days 7 and 28. Results Over the 7-month study period, April to October 1996, a total of 766 subjects were screened for entry; 455 were confirmed smear-positive for P. falcipanrnz. 107 for P. vivax, and 3 for mixed infections. A total of 380 falciparum malaria patients were followed through day 28, of whom 222 were in the interven- tion group (artesunate + mefloquine) and 158 in the placebo group (artesunate and paracetamol). Table 1 summarizes the results. All patients were followed up at home on days 7 and 28 by the local health assistants. On day 28, only one patient in the mefloquine group and seven in the paracetamol group remained slide-positive for P. falcipanunr. These were regarded as treatment fail- ures. The failure rate for mefloquine was 0.45% (95% Cl = 0.0-2.5) and for paracetamol (placebo) 4.4% (95% CI = 1.8-9.0). The result is statistically significant (Fisher's test, P = 0.01). No patient in either group developed severe or complicated malaria, nor were any toxic effects shown. One patient from each group was hospital- ized- in the mefloquine group due to giddiness and vomiting; both patients completed their treatments in the hospital and recovered fully. Another five pa- tients from the mefloquine group complained of gid- diness but required no medical intervention. Compliance was measured by urine tests for chloroquine and quinine (used as biological mark- ers) and by asking to see the blister packs following treatment. The compliance rate (full course of treat- ment) for both groups was 99.5% (378/380), only one patient in each group failing to complete the full treatment (negative urine test). Discussion The above results suggest that blister packs are highly acceptable (close to 100% acceptance) to WHO Bulletin OMS. Vol 76 (Suppl. 1) 1998 39 Tin Shwe et al. malaria patients and to dealers at the township level. It would appear that the combined packaging of drugs promoted their purchase by patients, com- pared with recommendations for independently pur- chasing two or more drugs with explanations of why multidrug therap.y is important. In the subsi- dized mefloquine intervention described above, multidrug purchases and compliance with therapy, without blister packs, was less than 5%. At the RHC (community) level, blister packs improved purchases and treatment compliance to nearly 100%. This has important implications for areas with increasing levels of multidrug-resistant P. fakiparum malaria, e.g. in the Thai-Myanmar border areas and nearby townships, where the management and control of malaria are a major problem. Since artemisinin derivatives are readily available in some townships near the Thai-China border area, misuse can further increase resistance to them. In addition, the first study above has shown that health personnel, including physicians, prescribed artemisinin derivatives with incorrect dosages. One question that remains unanswered is the impact of giving proper dosing instructions, like those in our blister packs. Our study provided both verbal and written instructions, and the blister packs were sold at a subsidized price. The price incentive could probably be discounted because a similar in- centive for mefloquine was offered in the subsidized mefloquine intervention with little effect. However, the impact of clear verbal instructions from the health provider to the patient and of simple written instructions has yet to be investigated independently of the advantages of using the blister pack. In the present study, the cure rate with artesunate, alone or in combination with mefloquine, was shown to be >95% for uncomplicated P. falciparum malaria. Other studies, showing high recrudescent rates (>40%), were carried out in hos- pitals where the patients received immediate treatment with other antimalarials that may have affected the outcome. As our study was community- based with patients who were unfamiliar -with artemsinin derivatives, their compliance and re- sponse to the drug or drug combination may have been higher. Conclusion The combination of artesunate + mefloquine in a blister pack, which was sold at full price, showed improved drug compliance and therapeutic effect, compared with artesunate alone. However, two points should be mentioned. First, as our patients took a complete 5-day regimen of artesunate, alone or in combination with mefloquine, a comparison of the difference in the efficacy of 3-day and 5-day courses cannot be made. This matter is now being studied. Second, treatment of P. falciparum malaria with artesunate, alone or in combina- tion with mefloquine, should be reserved for slide-confirmed rather than clinically diagnosed cases. Resume Traitement communautaire du paludisme A falciparum non compIlqu6 au Myanmar: influence du conditlonnoment sous plaquette thermoformee sur 1'efficacit6 de I'association artesunate + m6floquine par comparaison avoc l'art6sunate seul On a effectu6 trois etudes afin de d6terminer la necessite, I'acceptabilite et l'efficacit6 d'une adjonction de m6floquine au traitement de premiere intention du paludisme A falciparum non compliqu6 par les d6riv6s de I'art6misinine (DA). Une etude r6trospective portant sur 255 agents de sant6 de base a montre que le fait de recommander des derives de I'artemisinine aux malades d6pendait de leur niveau de formation. Aucun des intervenants param6dicaux ni aucune sage-femme ne les a prescrits et seuls 9% des 129 m6decins l'ont fait, personne n'ayant conseille I'association DA plus m6floquine; 72% des malades ont pris des traitements trop courts pour permettre une gu6nson parasitologique. Afin de promouvoir l'adjonction de m6floquine aux sch6mas therapeutiques pr6conisant les DA, nous avons organis6 des ate- liers d'intervention avec les prestateurs de soins de sante et assum6 le coOt de la m6floquine pour les malades. Dans la deuxieme 6tude, nous avons interrog6 200 malades avant et apres l'intervention afin d'6valuer l'observance des doses completes de DA et l'utilisation de la m6floquine qui leur 6tait offerte. Apres l'intervention nous nous sommes apergus que seuls 3,6% d'entre eux avaient utilis6 la m6floquine et que 62% avaient pris des doses non curatives de DA. Dans la troisieme etude, nous avons foumi des doses quotidiennes de m6dicaments sous plaquettes thermoform6es ("blister") et avons compar6 la prise de DA + pla- cebo (158 malades) a celle de DA + m6floquine (222 malades) pendant 5 jours. Pour ces deux sch6mas th6rapeutiques, l'observance a 6t6 de 99%. Les gouttes epaisses au 28@ jour ont montr6 un sujet positif dans le groupe ayant requ un DA + WHO Bulletin OMS. Vol 76 (Suppl. 1) 199840 Efficacy of artesunate + mefloquine in Myanmar m6floquine contre 7 dans le groupe DA seul. Nous en avons conclu que le fait de foumir des doses quotidiennes sous plaquettes therrnoform6es permet d'ameliorer de fa9on trbs sensible l'observance des traitements de courte dur4e par des associations m4dicamenteuses, m4me si I'accroissement d'efficacit6 de l'association dans cette 6tude particuliere effectuee au Myanmar est rest6 marginal. References 1. Tin Shwe, Kyaw Win. Clinical trials of artemether and artesunate in the treatment of faiciparum malaria in Myanmar. Abstract in: Artemisinin Meeting: abstracts and programme. London, The Wellcome Trust, 1993: 14-15. 2. Ko Ko Hia et al. The study of the efficacy and safety of oral dihydroartemisinin tablet (Cotecxin) on uncom- plicated Plasmodium falciparum malaria patients. In: Abstracts of papers presented at the Myanmar Medi- cal Association Speciality Conference, Mandalay, 1995. 3. Sabai et al. Dihydroartemisinin (Cotecxin) in uncom- plicated falciparum malaria. In: Abstracts of papers presented at the 41" Myanmar Medical Conference, Yangon, 1995. 4. Sabel et al. Pattem of mefloquine efficacy in uncom- plicated falciparum malarla 1991-1994, D.S.G.H. Mingaladon. In: Abstracts of papers presented at the 71h Medical Specialities Conference, Myanmar Medi- cal Association, Mandalay, 1995. 5. Bunnag D et al. Clinical trial of artesunate and artemether on multidrug-resistant falciparum malaria in Thailand: a preliminary report. Southeast Asian joumal of tropical medicine and public health, 1991, 22: 380-385. 6. Looareesuwan S et al. Randomised trial of artesunate and mefloquine alone and in sequence for acute uncomplicated falciparum malaria. Lancet, 1992, 339: 821-824. 7. Looareesuwan S. Overview of clinical studies on artemisinin derivatives in Thailand. In: Artemisinin Meeting: abstracts and programme. London, The Wellcome Trust, 1993: 16-17. 8. Luxembourger C et al. Single-day mefloquine combi- naton in the treatment of multidrug-resistant falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1994, 88: 213-217. 9. Olnghaosu Antimalarial Coordinating Research Group. Antimalarial studies on qinghaosu. Chinese medicaljoumal, 1979, 92: 811-816. 10. Tin Shwe et al. Intervention study to improve the misuse of artemisinin and its derivatives at a township in Myanmar. In: Abstracts of papers presented at the 42nd Myanmar Medical Conference, Yangon, 1995. 11. World Health Organization. The role of artemis- inin and its derivatives in the current treatment of malaria (1994-1995). Report of an informal WHO consultation, held in Geneva, 27-29 September 1994. 12. Bruce-Chwatt LJ. Chemotherapy of malaria, 2nd ed. Geneva, World Health Organization, 1986: 195. WHO Bulfetin OMS. Vol 78 (Suppl. 1) 1998 41