Atovaquone and proguanil versus pyrimethamine/sulfadoxine for the treatment of acute falciparum malaria in zambia

CLINICAL THERAPEUTICSVVOL. 21, NO. 5, 1999

Atovaquone and Proguanil Versus PyrimethamineBulfadoxine for the Treatment of Acute Falciparum Malaria in Zambia

Modest Mulenga, MB,’ Thomas Y. Sukwa, MB, ChB, MPH, DrPH,’ Craig J. Canfield, MD,2 and David B.A. Hutchinson, MB3 ‘Tropical Diseases Research Centre, Ndola, Zambia, Africa, 2Pharmaceutical Systems Inc., Talent, Oregon, and 3Glaxo Wellcome Research and Development, Greenford, Middlesex, United Kingdom

ABSTRACT

Atovaquone and proguanil hydrochloride are blood schizonticides that demonstrate in vitro synergy against drug-resistant strains of Plasmodium falciparum. When coadministered, they may therefore be effective for the treatment of malaria in regions where there is known or suspected drug resistance. In an open-label, randomized, parallel- group, clinical trial conducted in Zambia, 163 patients (age range, 14 to 54 years) with acute P falcipantm malaria were randomly assigned to receive treatment with atovaquone and proguanil hydrochloride (1000 and 400 mg, respectively, administered orally at 24-hour intervals for 3 doses; n = 82) or pyrimetbamine/sulfadoxine (75/1500 mg administered orally as a single dose; n = 81). Efficacy was assessed by cure rate (the percentage of patients in whom parasitemia was eliminated and did not recur

Accepted for publication March 2, 1999. Printed in the USA. Reproduction in whole or part is not permitted.

during 28 days of follow-up), parasite clearance time (PCT), and fever clearance time (FCT). Safety was determined by se- quential clinical and laboratory assessments over 28 days. Cure rates did not differ significantly between patients treated with atovaquone and proguanil (100%) and those treated with pyrimethamine/ sulfadoxine (98.8%). Patients in the atovaquone and proguanil group had a significantly shorter FCT than patients in the pyrimetbamine/sulfadoxine group (mean, 30.4 vs 44.9 hours; P < 0.05) but a longer PCT (mean, 64.0 vs 5 1.4 hours; P < 0.05). Both treatments were well tolerated; adverse events and laboratory abnormalities were typical of those normally observed in patients with malaria. In this study, the combination of atovaquone and proguanil was equally effective and as well tolerated as pyrimethaminekulfadoxine for the treatment of acute, uncomplicated, drug- resistant falciparum malaria in Zambia. Key words: atovaquone, proguanil, pyrimethamine, sulfadoxine, Plasmodium falciparum malaria.

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INTRODUCTION tients with acute falciparum malaria in Zambia.

Plasmodium falciparum malaria has be- come a problem of increasing magnitude in Africa due to the development of mul- tidrug resistance. Formerly, chloroquine was curative of falciparum malaria in most Africans. However, during the 1980s the cure rate with chloroquine began to fall; in Zambia, cure rates were 56% in 1985 and 37% in 1989-1990.‘,*

Alternatives to chloroquine (eg, pyrimethamine with sulfadoxine, mefloquine with pyrimethamine/sulfadoxine, and halofantrine) have proved highly effective in the treatment of falciparum malaria in Zambia, with reported cure rates ranging from 96% to 1OO%.2,3 However, substan- tial safety risks may be associated with these therapies. Pyrimethamine/sulfadoxine has caused severe and sometimes fatal cases of Stevens-Johnson syndrome,4 epi- dermal necrolysis,5 and hepatic necrosis.(j Mefloquine has been linked with severe neuropsychiatric disturbances,7*8 and halofantrine can cause cardiotoxicity manifested by arrhythmias and prolongation of the QT interval.9,10

Atovaquone, a hydroxynaphthoquinone that inhibits plasmodial mitochondrial electron transport,” and proguanil hydrochloride, an isopropylbiguanide that inhibits plasmodial dihydrofolate reduc- tase (primarily through its metabolite, cy- cloguanil),t2 act synergistically as blood schizonticides.13 In several previous studies,14-16 the combination of atovaquone and proguanil has been well tolerated and effective in the treatment of acute, uncomplicated falciparum malaria.

The objective of the present study was to compare the efficacy, safety, and toler- ance of atovaquone and proguanil with those of pyrimethamine/sulfadoxine in pa-

PATIENTS AND METHODS

Patient Population

All study participants were inpatients at the Central Hospital of the Tropical Diseases Research Centre in Ndola, Zam- bia. Patients were included in the study if they had acute, uncomplicated falciparum malaria with parasite counts ranging from 1000 to 2OO,OOO/pL, were between 12 and 65 years of age, weighed at least 40 kg, and had no underlying diseases. Patients were excluded from the study if they were pregnant or breastfeeding or had mixed infections, persistent vomiting, or inter- current febrile infections. Patients were to be withdrawn from the study if their clinical condition deteriorated, their con- sciousness became impaired, they showed no significant reduction in parasitemia within 48 hours of starting treatment, they had recrudescent parasitemia, or they ex- perienced a serious adverse event. The protocol was reviewed and approved by the institutional review board at the study site. All patients or their guardians gave written informed consent.

Study Design

This Phase III comparative clinical trial, conducted between December 1993 and May 1994, had an open-label, randomized design. Patients were admitted to the study sequentially. If they had received incom- plete antimalarial treatment before admission and were not acutely ill, patients were carefully observed until parasitemia began to increase and they became febrile. Pa- tients remained in the hospital during treatment and for a 28-day follow-up period.

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Patients were randomly assigned to receive either four 250-mg tablets of atovaquone (total, 1000 mg/d) coadministered with four lOO-mg tablets of proguanil hydrochloride (total, 400 mg/d) once daily for 3 days, or 3 tablets each containing 25 mg pyrimethamine and 500 mg sulfadoxine, administered as a single dose. Be- cause pharmacokinetic studies have shown that ingestion of food increases atovaquone’s bioavailability,17 the atovaquone and proguanil regimen was administered approximately 45 minutes after ingestion of a liquid meal. Patients who vomited within 1 hour after a dose received another dose of study drug. All antimalarial drugs were administered under supervision of the investigators.

Clinical Assessment and Efficacy End Points

Clinical examinations and an inquiry about symptoms were performed at least once daily for the first 7 days and on days 14,21, and 28 after the start of treatment. Pulse and oral temperature were measured every 4 hours until they had been normal for 2 days.

The primary efficacy end point was the 28-day cure rate; only patients whose out- come at day 28 was known could be evaluated for efficacy. Assessment of the response to treatment was based on the World Health Organization classifica- tion.18 A sensitive (S) response was defined as parasite clearance within 7 days without recrudescence during the 28-day follow-up period. Resistant responses were subdivided into R 1 (parasite clearance within 7 days, followed by recrudescence within 28 days), R2 (marked reduction of parasitemia but without clearance within 7 days), and R3 (no significant reduction of

parasitemia during the first 48 hours). Pa- tients were classified as unassessable and excluded from the analysis of 28-day cure rates if they were withdrawn from the study or were not followed for ~28 days (even if they were aparasitemic and clinically well when last seen). Cure rates were calculated from the ratio of S responses to the total of S, Rl , R2, and R3 responses.

Parasite clearance time (PCT) and fever clearance time (FCT) provided corrobora- tive evidence of efficacy. PCT was calculated from initiation of antimalarial treatment until the first time that peripheral blood films were negative for asexual parasites. FCT was similarly calculated from initiation of treatment until body temperature had decreased to 37.5 “C and remained no higher than 37.5 OC for 224 hours.

Laboratory Assessments

Parasite counts were determined from thick blood films prepared every 6 hours until 3 films were negative. Thereafter, blood films were prepared daily until day 7 and weekly until day 28. The films were stained with Giemsa stain and the number of asexual parasites per 200 white blood cells counted, with the results expressed as parasites per microliter of blood. A thick film was considered negative only after the examination of 200 oil-immersion fields showed no parasites. Blood films were interpreted by a technician who was unaware of treatment assignment.

Blood was obtained for routine hematology and clinical chemistry studies before treatment and on study days 3,7,14, and 28. Hematologic variables tested were hematocrit, hemoglobin, red blood cell count, white blood cell count and differ- ential, and platelet count. Clinical chemistry tests included glucose, blood urea

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nitrogen, creatinine, total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and albumin. Blood was also obtained before treatment for an assay of glucose-6-phosphate dehydrogenase (G6PD) status. Routine uri- nalyses were performed before treatment and on day 7. Stool specimens were ex- amined for ova and parasites.

Safety Analysis

Data from all study participants were used in the safety analysis. Adverse experiences, defined as any clinical finding that first occurred or increased in intensity within 10 days after treatment initiation, were identi- fied from signs and symptoms recorded at clinical assessments. Information regarding the duration of the adverse experience, its intensity, its severity, its attributability to the study drug (as judged by the investigator), and any action taken was also collected. Laboratory abnormalities that fust occurred or increased in intensity after the start of treatment were also evaluated.

Statistical Analysis

For each treatment group, descriptive statistics (mean, SD, median, and range) were calculated for continuous demographic variables and initial physical find- ings. For discontinuous variables, the rate or percentage of abnormality was determined. Geometric means were calculated for initial parasite counts. Differences in baseline characteristics were compared by analysis of variance. The Yates corrected chi-square analysis19 was used to compare differences in cure rates between treatment groups and to calculate 95% confidence intervals. The Mann-Whitney U test was used to calculate differences in

medians, with 95% confidence intervals, for FCT and PCT, and for hematology and biochemistry test results at each time period. A difference was considered statisti- cally significant if P was cO.05.

RESULTS

Patient Characteristics

One hundred sixty-three patients with acute, uncomplicated falciparum malaria were randomized to treatment with atovaquone and proguanil (n = 82) or pyrimethamine/sulfadoxine (n = 81). A total of 160 patients (98%, 80 in each treatment group) completed the study and were as- sessable. Of the 3 unassessable patients, 1 was found to have tuberculosis 3 days after completing his treatment with atovaquone and proguanil and was withdrawn by the investigator. The father of 1 patient withdrew consent without explanation after the patient had received 2 doses of atovaquone and proguanil. The third patient left the ward 8 days after completing treatment with pyrimethamine/sulfadoxine and did not re- turn. The remaining 160 patients remained in the hospital for the full duration of follow-up. No patient died during the study.

The conduct of the study complied with the protocol with 2 exceptions: 1 patient had a mixed infection with Plasmodium ovale and was inadvertently included in the study, and 1 patient had a baseline parasite count below the minimum defined by the protocol (<lOOO/bL). The response to treatment of these patients was indistinguishable from that of other patients, and they were not withdrawn.

The 2 treatment groups were similar with respect to all demographic characteristics. All patients were black and almost all were male (Table I). There were no clinically

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Table I. Demographic characteristics and baseline signs and symptoms.

Variable

Atovaquone Pyrimethamine/ and Proguanil Sulfadoxine

(n = 82) (n = 81)

Sex (n) Male Female

Black (n) Age, y (mean f SD)

Range Height, cm (mean f SD) Body weight, kg (mean f SD) Temperature, “C (mean f SD)

Highest before treatment Parasite count/p,L (geometric mean)

Range G6PD deficiency, no. of patients (%) Malarial signs, no. of patients (%)

Fever Splenomegaly Lymphadenopathy Rash Hepatomegaly Jaundice Heart abnormality

Malarial symptoms, no. of patients (%) Headache Chills/rigors Arthralgia Dizziness Myalgia Anorexia Abdominal pain Nausea Insomnia Weakness Cough Palpitations Vomiting Chest pain Frequent urination Diarrhea

80 2

82 25.9 f 7.8

14-49 170 + 7.0

56.3 + 7.2 37.8 + 1.1

40.2 14,799

872-61,813 9 (11)

52 (63) 29 (35) 26 (32) 13 (16) 7 (9) 6 (7) 3 (4)

75 (91) 69 (84) 54 (66) 37 (45) 39 (48) 37 (45) 35 (43) 37 (45) 34 (41) 27 (33) 25 (30) 21 (26) 18 (22) 10 (12) 13 (16) 15 (18)

79 2

81 24.9 f 7.6

16-54 169 + 6.8

53.6 f 6.9 38.1 f 1.2

41.0 18,112

1525-74,817 12 (15)

60 (74) 24 (30) 22 (27) 15 (19) 6 (7) 2 (2) 3 (4)

75 (93) 75 (93) 48 (59) 41 (51) 39 (48) 39 (48) 39 (48) 33 (41) 32 (40) 35 (43) 31 (38) 26 (32) 16 (20) 16 (20) 13 (16) 9 (11)

G6PD = glucose-6-phosphate dehydrogenase.

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Table II. Pretreatment laboratory results.

Laboratory Test

Atovaquone and Proguanil (n = 82)

Mean Abnormal*

Pyrimethamine/Sulfadoxine (n = 81)

Mean Abnormal*

Hemoglobin (g/dL) 13.7 Hematocrit (%) 40.9 Red blood cell count (x 1 Oi2/L) 4.4 White blood cell count (x109/L) 6.2

Neutrophils (%) 61.4

Lymphocytes (%) 36.9

Monocytes (%) 0.5 Eosinophils (%) 1.1 Basophils (%) 0.2 Platelets (x 1 09/L) 332 BUN (mmol/L) 5.5 Creatinine (pmol/L) 96.5 Glucose (mmol/L) 6.2 Albumin (g/dL) 4.0 Bilirubin (pmol/L) 20.1 AST (U/L) 36.7 ALT (U/L) 21.3

28 (34) L 21 (26) L 25 (30) L

9 (11) L 2 (2) I-I 7 (9) I.

13 (16) H 5 (6) L

21 (26) H 0 (0) H 1 (1) H 1 (1) H 0 (0) L

10 (12) H 7 (9) H

35 (43) H 14 (17) L 32 (39) H 16 (20) H

8 (10) H

13.4 40.0

4.2 6.2

65.9

32.4

0.7 1.0 0.1

320 6.0

103.1 6.4 4.0

22.6 38.1 27.2

32 (40) L 26 (32) L 35 (43) L 12 (15) L 0 (0) H 4 (5) I.

24 (30) H 16 (20) L 14 (17) H 0 (0) I-I 1 tl)H 0 (0) I-I 1 (1) L 9 (11) H

14 (17) H 38 (47) H 13 (16) L

40 (49) H 21 (26) H

5 (6) H

BUN = blood urea nitrogen; AST = aspartate aminotransferase; ALT = alanine aminotransferase. *L = below normal, H = above normal; values in parentheses are percentages.

significant differences between groups with regard to baseline signs and symptoms (Table I) or pretreatment laboratory values (Table II). A modest degree of anemia was present in approximately one third of patients. The premalaria health status of all patients was considered good, and none of the patients had cerebral malaria. One patient developed severe malaria with renal insufficiency that required peritoneal dialy- sis after treatment with pyrimethamine/ sulfadoxine. Thirty-four patients (2 1%) had a history of vomiting at admission; in no case was the vomiting considered severe enough to prevent oral therapy.

The types of medications taken con- comitantly by patients during the study did not differ between the atovaquone-and-proguanil and pyrimethamine/sulfadoxine groups (data not shown). The most common concomitant agents were acetamino- phen (66% and 79%, respectively) and promethazine (9% and lo%, respectively).

E&acy

By day 28 after treatment, 100% of as- sessable patients in the atovaquone-and- proguanil group and 98.8% of patients in the pyrimethamine/sulfadoxine group

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M. MULENGA ET AL.

Table III. Therapeutic response at day-28 evaluation.

Atovaquone and Pyrimethamine/ Proguanil Sulfadoxine

No. of patients with 28-day follow-up No. (%) of patients cured Fever clearance time (h)*

Median Mean (SD) Range

Parasite clearance time (h)’ Median Mean (SD) Range

80 80 80 (100) 79 (98.8)

23 48 30.4 (28.2) 44.9 (2 1.2)+

l-160.5 6-101

72 48 64.0 (21.7) 51.4 (21.0)‘1

12-102 6-114

*Fever clearance time was analyzed in 67 patients in the atovaquone-and-proguanil group and in 77 patients in the pyrimethaminekulfadoxine group.

+Significant difference between treatment groups (P < 0.05).

*Parasite clearance time was analyzed in 81 patients in each treatment group.

were cured (Table III). The difference in cure rates was not significant. The patient who was not cured after treatment with pyrimethaminelsulfadoxine had an Rl pat- tern of resistance. The atovaquone-and- proguanil group had a significantly shorter FCT than did the pyrimethamine/sulfadoxine group (mean, 30.4 vs 44.9 hours; P < 0.05) and a significantly longer PCT (mean, 64.0 vs 5 1.4 hours; P < 0.05) (Table III). The 95% confidence intervals for the differences in the medians of the FCT and PCT were 8.3 to 26.5 hours and 12 to 24 hours, respectively.

Safety The adverse experiences reported were

typical of malaria symptoms. In descend- ing order of frequency, the 4 most common adverse experiences in the atovaquone-and-proguanil group were headache (46%), abdominal pain (35%), weakness (28%), and diarrhea (26%); the 4 most

common adverse experiences in the pyrimethamine/sulfadoxine group were abdominal pain (42%), headache (37%), weakness (19%), and orthostatic hypotension (17%). Vomiting occurred with equal frequency in the atovaquone-and-proguanil and pyrimethaminelsulfadoxine groups (12% vs 15%). Vomiting within 1 hour of dosing necessitated readministration of a dose in 3 patients receiving atovaquone and proguanil and 1 patient receiving pyrimethamine/sulfadoxine. In terms of adverse experiences that were judged possibly drug related, there were no significant differences between treatment groups (Table IV).

In most patients, laboratory abnormalities improved after starting treatment. Of those laboratory abnormalities that occurred after the start of treatment, all were of the type commonly seen in evolving malarial infections (Table V). Only 1 of 5 patients who had significant decreases in hematocrit, hemoglobin, or red blood cell count

847


Table IV. Adverse events (%) reasonably or possibly related to treatment.

Adverse Event Atovaquone and Proguanil Pyrimethamine/Sulfadoxine

(n = 82) (n = 81)

Headache Abdominal pain Weakness Diarrhea Vomiting Myalgia Orthostatic hypotension Nausea Dizziness Anorexia Hepatomegaly Pruritus Splenomegaly Palpitations

23 (28) 24 (30) 23 (28) 17 (21) 19 (23) 13 (16) 13 (16) 9 (11) 10 (12) 13 (16) 8 (10) 5 (6) 6 (7) 14 (17) 6 (7) I1 (14) 6 (7) 9 (11) 6 (7) 4 (5) 5 (6) 5 (6) 4 (5) l(l) 3 (4) 2 (2) 3 (4) cl (0)

Table V. Number (%) of patients developing clinically significant laboratory abnormalities during the study.

Laboratory Test

Atovaquone and Proguanil Pyrimethamine/Sulfadoxine (n = 82) (n = 81)

Abnormality Abnormality Anytime After Abnormality Anytime Abnormality

Criterion Treatment at Day 28 After Treatment at Day 28

Hematocrit <25% Hemoglobin <7.5 gldL Red blood cell count <3 x 1012/L White blood cell count 13 x 109/L Neutrophil count <I x 109/L Bosinophil count >lOOO/pL BUN ~-25 mg/dL Creatinine >2 mg/dL Albumin <3 gldL Proteinuria r2+ Hematuria r2+ ALT >lOO u/L AST >lOO u/L

l(l) 0 (0) l(l) 2 (2)

14 (17) 10 (12) 3 (4) 2 (2)

11 (13) 3 (4) 2 (2) 3 (4) 3 (4)

0 (0) 0 (0) 0 (0) 0 (0) 4 (5) 8 (10) 0 (0) 0 (0) 4 (5) 0 (0) 0 (0) l(1) 0 0

2 (2) 2 (2) 2 (2) 8 (10)

17 (21) 7 (9) 3 (4) 2 (2)

12 (15) 3 (4) 1 (1) 5 (6) 4 (5)

l(l) l(l) 0 (0) 3 (4) 4 (5) 6 (7) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)

BUN = blood urea nitrogen; ALT = alanine aminotransferase; AST = aspartate aminotransferase.

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M. MULENGA ET AL.

was deficient in red blood cell G6PD; this patient had received pyrimethamine/sulfadoxine. Neutropenia was reported in both treatment groups and later resolved sponta- neously. Eosinophilia developed frequently after initiation of each treatment group. This was attributed to the fact that approximately 28% of patients had 1 or more intestinal parasites, the most common being Ascaris lumbricoides (24%), Schistosoma mansoni (5%), and hookworm (4%). Treatment for intestinal parasitism was delayed until the second or third week of follow-up.

Hypoalbuminemia was also seen in both treatment groups; this was probably related to nutritional deficiencies in the study population. Clinically significant changes in liver function (manifested by enzyme abnormalities) were relatively uncommon. Elevation of ALT and AST levels occurred in similar percentages of patients in the atovaquone-and-proguanil (4% and 4%, respectively) and pyrimethamine/sulfadoxine (6% and 5%, respectively) groups. Only 1 patient (an atovaquone and proguanil recipient) had a markedly elevated ALT level 28 days after treatment. This was not considered drug related.

DISCUSSION AND CONCLUSIONS

The results of this study indicate that a regimen of atovaquone in combination with proguanil once daily for 3 days is as effective as a single dose of pyrimethamine/ sulfadoxine for the treatment of falcipamm malaria in a region where chloroquine resistance is common. In view of the 100% cure rate observed with atovaquone and proguanil, this combination should be thought of as an important therapeutic al- ternative to chloroquine or other antimalarial therapies that are no longer effective due to parasite resistance.

The atovaquone and proguanil regimen assessed in the present study has resulted in cure rates of 94% to 100% against falciparum malaria in clinical trials conducted in diverse geographic locations?0 In the Philip- pines, atovaquone and proguanil treatment resulted in a significantly higher cure rate (100%) than either chloroquine alone (30%) or chloroquine plus pyrimethamine/sulfadoxine (88%)?l The lower cure rate with pyrimethamine/sulfadoxine in the Philip- pines reflects a higher incidence of parasite resistance to this combination in that coun- try compared with the area of Zambia where our study was conducted.

Zambia is one of the few countries in which resistance to pyrimethamine/sulfadoxine has not been reported to be a significant problem. However, resistance has increased in many other African countries in the 199Os, with a high incidence of pyrimethamine/sulfadoxine resistance in Zaire (65%)?2 Ghana (37%),z3 Equatorial Guinea ( 14%)F4 and Uganda ( 12%).25 Widespread P falciparum resistance has also been reported in Southeast Asia, Western Oceania, and South America.26

Patients treated with atovaquone and proguanil had a shorter FCT (mean, 30.4 hours) but longer PCT (mean, 64.0 hours) than those treated with pyrimethamine/ sulfadoxine. Both values were within the range reported for atovaquone plus proguanil in other clinical trials (FCT, 27 to 39 hours; PCT, 47 to 72 hours)?O and the clinical importance of shorter or longer clearance times is unclear. Clearance times may be influenced by differences in patients’ prior experience with malaria (im- munity), level of infection (reflected by initial parasite counts), use of antipyretics (with respect to FCT), and state of nutri- tion . The parasitologic cure rate is the most clinically important measure of efficacy.

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CLINICAL THERAPEUTICS*

The combination of atovaquone and proguanil was as well tolerated as sulfa- doxinelpyridoxine in this study. The most frequently observed adverse events and laboratory abnormalities are common manifestations of malaria, and it is diffi- cult to determine which events might have been related to therapy. No patient in either treatment group had an adverse event that required discontinuation of therapy.

The 2 antimalarial combinations evaluated in this study differ with regard to their spectrum of clinical utility. Because pro- phylactic regimens have been associated with serious and sometimes fatal sulfon- amide-related toxicities,s,6 pyrimethamine/ sulfadoxine is now used only for the treatment of malaria. In contrast, the combination of atovaquone and proguanil is useful not only for the treatment of acute malaria but also for prophylaxis?738 Thus the combination of atovaquone and proguanil is an important option for the treatment and prophylaxis of falciparum malaria.

ACKNOWLEDGMENTS

This study was supported by a grant from Glaxo Wellcome Research and Develop- ment, Greenford, Middlesex, United Kingdom.

The authors thank the patients and staff who participated in this study.

Address correspondence to: David B.A. Hutchinson, MB, c/o Jeffrey D. Chulay, Glaxo Wellcome Inc., 5 Moore Drive, Research Triangle Park, NC 27709.

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Atovaquone and proguanil versus pyrimethamine/sulfadoxine for the treatment of acute falciparum malaria in zambia