The study included 204 male patients with P. falciparum malaria (age range, 15 to 64 years; mean ± standard deviation [SD] age 25.8 ± 9.5 years). These patients were randomized to three treatment groups (n = 68 each; Table ). The majority of patients (n = 157; 77%) came from the western border of Thailand, where the most multidrug-resistant P. falciparum parasites are prevalent. Less than half the patients (n = 92; 45%) had a history of malaria. There were no significant differences in age or geographic distributions, parasite counts on admission, or incidence of previous malaria attacks between the three treatment groups, (P ≥0.09) (Table ). Elevated serum bilirubin levels (total bilirubin concentration, ≥3 mg/dl) were noted in 26 patients (Q7 group, n = 13; Q7C7 group, n = 10; Q7T7 group, n = 3). None of these patients had any other complications, and all came from areas where malaria is endemic. The overall total bilirubin levels for the Q7C7 and Q7 groups on admission were not different (P = 0.68), but the levels for both groups were slightly higher than those for the Q7T7 group (P ≤ 0.004). Other baseline laboratory findings (Table ) were not statistically significant among the groups studied. None of the patients had or developed severe anemia (hematocrit, >15% for all patients) or elevated serum creatinine levels (serum creatinine levels, <3 mg/dl for all patients) or other complications of malaria.
TABLE 1 Laboratory findings on admission for patients with P. falciparummalaria Clinical response.
Clinical recovery following treatment occurred in all patients (Table ). FCTAs ranged from 2 to 100 h (median, 8 h) and were not significantly different between the three treatment groups (P = 0.10). The overall median (range) FCTB was 48.0 h (4 to 152 h). As shown in Fig. , the FCTBs for the two combination regimens (Q7C7 group, 47 h; Q7T7 group, 36 h) were not significantly different (P = 0.08), but the FCTBs for both combination regimens were significantly shorter than the FCTB for the Q7-only regimen (56 h) (P ≤0.005). Patients admitted with hyperbilirubinemia had significantly longer FCTs (median, 72 h; range, 8 to 124 h) than those for the remaining patients (median, 48 h; range 7 to 152 h) (P = 0.014). After stratification for jaundice on admission, the FCTBs for the two combination regimens remained not significantly different (Q7C7 = 44 h, Q7T7 = 36 h [P = 0.32]), and the FCTBs for both combination regimens were significantly shorter than the FCTB for the Q7-only regimen (53 h) (P ≤ 0.012).
Cumulative fever clearance rates for the three treatment groups of patients with P. falciparum malaria.
PC and parasite reduction.
Following the start of treatment, the overall mean ± SD PCT was 77.7 ± 22.8 h. Between the treatment groups, there were no significant differences in PCTs (P = 0.98), and this remained after stratification for jaundice on admission (P = 0.82). There were also no significant differences in PRRs or clearance of parasitemia for the groups studied, as assessed from the PC50, the PC90, and the calculated PRRs (PRR24, PRR48, and PRR96) (P ≥0.65) (Table ). The overall PCT for all patients correlated directly with the PC50 and PC90 (r = 0.34 and 0.68; respectively; P ≤ 0.001) and inversely with the calculated PRRs (PRR24 and PRR48; r = 0.31 and 0.42, respectively; P < 0.001). There were weak but statistically significant correlations between PCT and FCTs (r = 0.24 for FCTA and r = 0.33 for FCTB; P <0.01).
TABLE 2 Clinical and parasitological responses in patients with P. falciparummalaria Clinical course.
Overall, 161 (79%) of the recruited patients completed at least 28 days of follow-up or remained in the hospital until the appearance of vivax or falciparum malaria (Table ). Of these 161 patients, 8 (5.0%) had a subsequent reappearance of falciparum malaria and another 33 (21%) had a delayed appearance of vivax malaria. Recrudescences of falciparum malaria were observed for patients who received the Q7-only regimen (n = 7; 13%) and in one patient treated with the Q7T7 regimen (2%) but not in patients treated with the Q7C7 regimen. The time to the onset of recrudescence ranged from 15 to 23 days (mean ± SD = 19.3 ± 2.5 days). The cure rates (i.e., no recrudescence of falciparum malaria) for the two combination regimens (98 and 100%) were both significantly higher than the cure rate for the Q7 regimen (87%) (P ≤ 0.04) (Fig. ).
TABLE 3 Clinical outcomes for monitored patients with subsequent appearances of malaria infection which occurred within 28 days after the start oftreatment
Cumulative cure rates for the three treatment groups of patients with P. falciparum malaria.
Cryptic infection with P. vivax was found in 33 (21%) patients. Despite the differences in the 28-day follow-up rates between the three groups, the rates of mixed infection among the three treatment groups were not significantly different (P = 0.9). The overall mean ± SD time taken for the appearance of vivax malaria was 23.7 ± 3.0 days and ranged from 16 to 28 days after the start of treatment. There was no significant difference in the time to the appearance of vivax malaria (within the 28-day follow-up period) between the two combination regimens (for Q7C7, 25.1 ± 1.4 days; for Q7T7, 24.8 ± 3.2 days [P = 1.0]), although the times to onset for both regimens were significantly delayed compared to the time to onset for the Q7 regimen (21.6 ± 3.0 days) (P ≤0.028). Of the 161 patients monitored, 16 patients returned for subsequent monthly follow-up and none had a reappearance of falciparum malaria, but five patients had later appearances of vivax malaria, between days 38 and 61. These late episodes of vivax malaria were found in all groups: Q7, n = 2; Q7C7, n = 2; Q7T7, n = 1.
Therapeutic responses in patients with subsequent recrudescences.
The eight patients with subsequent recrudescences had significantly longer FCTs (83.5 ± 44 versus 50.4 ± 31.1 h [P = 0.023]) and PCTs (95.4 ± 21.1 versus 77.2 ± 21.8 h [P = 0.005]) than those for patients with no recrudescence. Only one of these patients had elevated serum bilirubin levels on admission; there was no association between bilirubinemia and recrudescent infections. Parasite counts on admission between patients with and without recrudescences were not significantly different (geometric mean of 21,875 and range of 4,019 to 141,300 versus geometric mean of 14,475 and range of 30 to 276,948 [P = 0.32]). Between patients with and without mixed P. vivax and P. falciparum infection, there were no significant differences in parasite counts on admission, FCTs, or parasitological responses (P ≥ 0.14).
Clinical and laboratory findings following treatment.
On admission, gastrointestinal symptoms were noted in 93 (46%) patients. Of these, 85 (91%) had nausea, 31 (33%) had vomiting, 27 (29%) had abdominal pain, and 3 (3.2%) had diarrhea. There were no significant differences in the incidences of gastrointestinal symptoms among the three treatment groups (P = 0.45). Following treatment, only six additional patients developed any of the gastrointestinal symptoms (n = 3 for Q7, n = 2 for Q7C7, n = 1 for Q7T7). These patients complained of nausea (n = 6) with or without vomiting (n = 4) or abdominal pain (n = 3) or diarrhea (n = 2). After starting antimalarial treatment, all patients recovered and the gastrointestinal symptoms disappeared within 1 to 7 days (median, 2 days).
The majority of patients (193; 93.7%) developed transient tinnitus. The onset of tinnitus usually occurred after 3 days of treatment. There were no significant differences in the incidences of cinchonism among the three treatment groups (P = 0.8). All 26 jaundiced patients had normalization of bilirubin levels after 7 days (23 of 26; 88.5%) or 14 days (3 of 26; 11.5%) of treatment. None of the studied patients developed allergic rashes or other serious adverse effects, as monitored by clinical symptoms and laboratory data (data not shown).