A clinical trial of halofantrine in acute uncomplicated malaria in Thai soldiers

Treatment of acute malaria in Thailand

21

A Clinical Trial of Halofantrine in Acute Uncomplicated Malaria in Thai Soldiers Sriwatana Chitchang and Subin Wongteptien

Summary This studywas performed on 84 Thai soldiers infected with either Plasmodium falciparum orP. vivax at Camp Chakrapongs Army Hospital,PrachinburiProvince, Thailand. Following treatment with halofantrine (three 500 mg doses at 6 h intervals), complete parasite clearance occurred within 53.6 h in all patients. Recrudescence of parasitaemia was not seen during 28 daysfolloui-up. Haematological and biochemical valueswerenot significantly altered by treatment. Nevertheless, a slight increase in white blood cell counts was observed post-treatment. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) leoels were slightly increased in some patients, but alkaline phosphatase was not affected. The enzymatic changes returned to normal by day 7. This study suggested that halofantrine hydrochloride at a dose of500 mgthree timesdailyat 6 lz intervals was highly effective and free from significant clinical and biochemical sideeffects whenusedfor the treatment of mild-to-moderate P. falci parum and P. vivax malariain an area wherechloroquine resistance is prevalent. Introduction quinine and tetracycline is now the best Malaria is still a major world health regimen for treating falciparum malaria problem especially in the tropics. in Thailand but it is expected that the Because of the increasing mobility of parasite will develop resistance to this human populations, more and more combination in the near future. Thereimported cases are found in malaria-free fore, the search for new compounds that countries and countries where malaria could be used as alternative antimalarial has been eradicated. Malignant tertian drugs is very urgent. The 9-phenanthrenemethanols were malaria (falciparum malaria ) has become increasingly resistant to almost all of the first evaluated in human subjects during antimalarial drugs available in Thailand World War II. Three compounds - chloroquine, sulfadoxine or sulfalenel emerged from these early studies that pyrimethamine (Bruce-Chwatt, 1981; showed promise as antimalarial agents. Harinasuta et al., 1967) and even The first, WR 33063, was found to be quinine (Jaroonvesama et al., 1974; effective in man for both chloroquineChongsuphajaisiddhi et al., 1981). The sensitive and -resistant strains of P. [al geographical distribution of the drug- ciparum (Arnold et al., 1973; Canfield et resistant strains has also increased al., 1973) although the duration of greatly in recent years. A combination of therapy was six days. Animal studies showed that halofantrine (WR 171669) was more active than WR 33063 and less toxic than the third compound, WR Department of Parasitology, Pramong Kutklao College of MedIcine. Bangkok, ThaI/and. 122455 .

22

Halofancrine in the treatment of multidrug-resistant malaria

patients. Clinically they were not severely ill. No other significant concomitant diseases were apparent on initial history and physical examination. Consent for participation in the study was given by the patients after the nature of the study and the risks involved had been explained. Assessment of general physical status, blood pressure, liver and spleen size, the presence or absence of headache, backache, dizziness, fever, chills, nausea, vomiting, and diarrhoea were recorded. Evaluation was repeated every day for the first seven days and then on days 14, 21 and 28. The patients who were eligible for study received three doses of 500 mg halofantrine hydrochloride at 6 h intervals. Five-miIlilitre samples of venous blood were obtained from all subjects in the study before dosage, on days 1-3, and on days 7, 14,21 and 28 post-treatment, for the measurement of haematocrit, haemoglobin, red blood cell (rbc) count, white blood cell (wbc) count and differential counts. Liver function profiles (SGOT, SGPT, total bilirubin, alkaline phosphatase) and renal function tests were obtained. Urine analysis for glucose, protein and blood (MULTISTIX) was performed at days 0, 3, 7 and 28. Parasite counts were performed on thin and thick films stained with Giemsa's and Field's stains, respec-

Halofantrine hydrochloride at a dose of 1 g daily for three days cured six out of six volunteers with chloroquineresistant and three out of three with chloroquine-sensitive falciparum malaria (Rinehart et al., 1976). Parasitaemia and fever cleared promptly. The most effective dosage regimen for clearance ofP. falciparum in man was 500 mg three times daily at 6 h intervals. At this dosage the drug was well tolerated in all subjects including patients with G6PD deficiency. Mild symptoms consisted of nausea, diarrhoea and epigastric distress. Haematology and clinical chemistry values remained within normal limits. The present study was designed to evaluate the efficacy of halofantrine at a dose of 500 mg three times daily at 6 h intervals and to investigate the safety of halofantrine hydrochloride in Thai patients with mild-to-moderate parasitaemia. Materials and methods The study was carried out at Camp Chakrapongs Army Hospital, Prachinburi, Thailand, 195 km north east of Bangkok, close to the border with Kampuchea. The study was conducted between November 1986and December 1987 and involved 84 patients. P. falciparum or P. vivax were present in thin and thick peripheral blood films in all

Table I. Demographic characteristics of patients classified by malaria type

Age (years) Height (cm) Weight (kg)

falciparum

vivax

25.8 ±9.52

24.67 ± 3.85

165.76 ± 6.2 56.96 ±7.51

167.57 ± 3.76 58.37 ± 6.0

Sex: Male Female

56

20

7

I

Total

63

2/

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Treatment of acute malaria in Thailand

Table 2. Distribution of parasite counts on inclusionaccording to malaria type

Parasite counts

falciparum

vivax

<10000

14

I

10000-100000

32

18

I00 000 - 200 000

13

2

200 000- 300 000

2

0

300 000 - 400 000

a

0

>400000

2

0

Total

63

21

Geometric mean

31571.18

32208.96

4.26

2.01

so

tively. The number of asexual parasites per 200 wbc on thick films or per 1000 rbc on thin films was counted, and the results expressed in terms of number of parasites per mrrr' blood. Blood smears for malarial parasites were obtained twice daily (at 9 am and 3 pm) for the first seven days and then at days 14, 21 and 28. All data were computerized. Descriptive and comparative statistics were prepared using the Statistics Package for the Social Sciences (SPSS). z-Independent tests were used to compare the time of parasite and fever clearances in P. falciparum and P. vivax malaria, whereas paired z-tests were used to compare the effects of the halofantrine on laboratory test values from day 0 to day 28 in the two types of malarial infections.

Results The study included 84 patients, 76 males and eight females (Table 1). In-

itially, parasitaemias ranging from 1403/ mm" to 474 SOO/mm3 (geometric mean, 29 853/mm3) were found in all 84 patients (Table 2). All had symptoms compatible with malarial infection. One patient had splenomegaly and one hepatomegaly. Of the 84 patients, six failed to complete the study. One (case no. 4) was withdrawn from follow-up after eight days when the parasite count began to increase after a short negative period. This patient was considered a treatment failure and treatment was switched to a 7-day quinine and tetracycline regimen resulting in resolution of the parasitaemia. Five patients were lost to followup (case nos 5,11,22,25,27) after 7, 21, 14, 1 and 7 days, respectively. Another patient (case no. 28) was withdrawn and received alternative treatment after all three doses of halofantrine were vomited up. Only 77 patients (56 with P. falciparum, 21 with P. vivax) were therefore available for full efficacy evaluation.

Table 3. Clearance times (11) (mean and so) according to malariatype

falciparum

vivax

t·test

Parasite clearance

52.97 ± 21.8

61.52 ± 17.2

P =0.109

Fever clearance

49.4 ± 23.5

42.29 ± 19.94

P = 0.219

24

Halofantrine in the treatment of mult idrug-reslscant malaria

Clearance 0/ parasites. Malaria trophozoites were satisfactorily cleared in all but one patient (case no. 4) within 96 h of treatment, the majority clearing within 48 h (Table 3). Four patients subsequently lost to follow-up also achieved para site clearance (case nos 5, ] 1,22,27) giving an overall response rate at day 7 of 80/81 (98.8%). Parasite clearance showed a trend towards longer times with increasing initial parasite counts (T able 4), but this was nor statistically significant. No recrudescence was seen in the 77 patients who completed 28 days follow-up. Fever also resolved rapidly in 71 patients who were febrile before treatment. Resolution of temperature occurred within 48 h in most cases (T able 3) . Clearance oJsymptoms and signs. Clinical manifestations compatible with acute malaria were present in all patients . Although many symptoms continued during resolution of malarial infection , no new symptoms were observed . Most symptoms such as nau sea , vomiting, diarrhoea and palpitations settled rapidly after treatment and often within the first day. Headache disappeared within 2-3 da ys while dizziness cantin ued for 3-5 days in several cases, often for some time after parasite clearance. Clinical jaundice was apparent in 15

cases before treatment. Resolution occurred in all of them within 1-3 days. Splenomegaly (2 em palpable) was presen t in only one patient (case no . IS ). By the third day after treatment the spleen was not palpable . Hepatomegaly was recorded in one patient (case no . 28) but there was no change in size during four days follow-u p. There were no significant changes in blood pressure . Before treatment , resting pulse rates in most patients (70 cases) were elevated (often markedly so) roughly in line with the fever. After treatment, pulse rates fell in parallel with the reduction of parasite count and fever. One patient (case no . 4) whose parasitaemia failed to clear , showed an initial fall in pulse rate but when the parasite count began to rise , so did the pulse . Clini cally significant abnormalities shown by laboratory tests did not develop after treatment in either P. f alciparum or P. uiuax malaria . Many patient s with both types of malaria were found to have abnormalities of bo th haematological and biochemical parameters before treatment. In cases of P. [alciparum malaria, clinical and statistically significant improvements in all parameters other than alkaline phos phatase were observed by the end of follow-up (T able 5) , with most abnormalities resolving within the first seven

Table 4. Comparison of parasite clearance times according to initial parasite counts

Baseline parasite count

falciparum

vivax

ii± so

ii±SO

n

< 10000

n

64.08 ± 13.52

12

72.0

I

10000- 100000

75.12 ± 2004

31

79.2 :!..: 16.08

18

10000 I - 200000

77.52 ± 14.4

13

84.0 ± 12.0

2

> 200000

90.0 ± 23.04

4

25

Treatment of acute malaria in Thailand

Table 5. Comparison of changes in laboratory tests pre-treatment and after 28 days follow-up in cases of P. (alciparum and P. vivsx malaria

Mean change day 28 - day 0 values ± so Laboratory test Haemoglobin

Units

Increasel decrease

g/d I

I

1.73 ± 1.12b

1.55± 1.30b

%

I

b

5.14 ± 3,54

4.57± 3.96 b

x 1011/1

I

0.75 ± O.4Sb

O.80± O.54b

b

Haematocrit Rbccount

9/1

Wbccount

x 10

Platelets

X

P. falciparum

P. vivax

patients

patients

0.54 ± 2.24'"

I

0.S5 ± 2.07

109/1

I

219.10 ± nAb

ALAT

IU

D

4.33 ± 15.37'

0.67 ± 11.07'"

ASAT

IU

D

5.0 I ± 12.87b

6.24 ± 16.73"'

IU

D

1.23 ± II.OS"'

4.00 ± 9.46'"

mg/dl

D

0.96± 1.20b

1.20± 1.54b

Alkaline phosphatase Bilirubin

219.30±S4.3I b

Abbreviations: I, increase in mean values; D, decrease in mean values. "' Not significant. 'p <0.05. bp <0.0 I (using paired t-test of the difference day 28 - day 0).

days. In cases of P. vivax malaria complete haematological recovery was observed, but significant improvement in liver function was not seen, other than in total bilirubin, as fewer abnormalities were present before treatment. Ofnote is the increase in total white cell counts after treatment (statistically significant in cases offalciparum malaria).

Discussion and conclusion Halofantrine hydrochloride at doses of 500 mg three times daily at 6 h intervals appeared to be highly effective in the treatment of P. falciparum and P. vivax malaria in 77 Thai soldiers who completed 28 days follow-up, with no recrudescence of parasitaemia during those 28 days. Only one case failed to respond to the treatment. The parasite clearance was 98.8% and the clearance time was rapid both for P. falciparum (52.97 ± 21.8 h) and P. vivax (61.57 ± 17.2 h). Fever clearance time was also

rapid both for P. falciparum (49.9 ± 23.5 h) and? vivax(42.29 ± 19.94 h). Most symptoms resolved rapidly within 24 h. However, headache and dizziness persisted slightly longer. Blood pressure remained stable throughout the course of treatment. Abnormalities shown by laboratory tests before medication were due to malarial infection and they resolved rapidly after treatment. Untoward side-effects and toxicity of halofantrine were not observed in this study, and overall treatment was well tolerated. Halofantrine hydrochloride in three 500 mg doses at 6 h intervals was thus highly effective and free from significant clinical and biochemical side-effects when used for the treatment of mild-tomoderate P. falciparum and P. vivax malaria. We conclude it is a suitable choice for treatment of acute malaria where the parasites show a high degree of multidrug resistance.

26

Halcfantrine in the treatment of multidrug-resistant malaria

Acknowledgements The authors are most grateful to Lieutenant General Singh a Saovaparp, the Surgeon General of the Royal Thai Army Medical Department for his kind permission to carry out this study in soldiers. Our special thanks go to Colonel Chaiyos Suthiboon and all of the medical and nursing staff and medical technicians at Camp Chakrapongs Army Hospital for their valuable assistance and cooperation. We thank Mrs ]anya Pattara-achachai for her processing of the data, and we thank Smith Kline & French for their generous supply of the drug for this study. Without their support this study would not have been possible. References

Arnold, D. D. et ai. (1973) A phenanthrcnerncthanol (WR 33063) [or treatment of acute malaria. Amimicrob. Agents Chemother. 3,207-213

Bruce-Chwatt, L.J. (1981) Chemotherapy of Malaria (2nd edn) WHO, Geneva Canfield, C.J. et al. (1973) Treatment of falciparum malaria [rom Vietnam with a phenanthrene methanol (WR 33063) and a quinoline methanol (WR 33090). AIllimicrob , Agellls Chemother, 3, 223-227 Chongsuphajaisiddhi, T., Sabcharocn, A., Attanath, P. (1981) In vitro and in vivosensitivity of falciparum malaria (0 quinine in Thai children. AnI!. Trap. Pediatr. 1,21-26 Harinasuta, T., Viravan, C. and Reid, H.A. (1967) Sulfamethoxin in chloroquine resistant falciparurn malaria in Thailand. Lancct l , 117 [aroonvesarna , N., Harinasuta , T. and Muangmanee, R. (1974) Recrudescence, poor response or resistance to quinine of falciparum malaria in Thailand. SE Asian]. Trap. Med. PublicHealth 5, 504 Rinehart, j., Arnold, J. and Canfield, C.]. (1976) Evaluation of two phenanthrene rnethanols for antimalarial activity in man, WR 122455 and WR 171669. Am. J Trap. Med. Hyg. 25, 769-774