There were 85 patients with acute vivax malaria 14–61 years of age (mean ± SD = 24.6 ± 10.1 years). The majority of patients acquired malaria infection from the western border of Thailand (N = 74, 87.1%) and a high proportion (N = 37; 43.5%) had had at least one malaria infection in the past year (median 2; range 1 to 10 attacks). All patients presented with a history of fever (median 4; range 1 to 20 days) before hospital admission. The geometric mean (range) peripheral blood P. vivax asexual parasite count was 6,205/µL (33 to 97,968/µL). Overall 29% (N = 25) of patients had detectable gametocytemia at presentation. The median (range) gametocyte count was 41/µL (16–110/µL). The majority of patients (88%) were thrombocytopenic (platelets < 180,000/µL) but none had significant abnormalities of other baseline hematology results (). Between the two treatment groups randomized to receive 30 mg or 60 mg primaquine daily for 7 days (N = 43 and 42), serum glutamic-pyruvic transferase (sGPT) concentrations were significantly higher in the high dose group (median 24; range 8 to 84 versus 19; 5 to 147 U/liter, P = 0.045) but all baseline characteristics and other laboratory findings were similar in the 2 groups (P ≥ 0.24).
Demographic data and therapeutic responses in patients with P. vivax malaria in a comparison of 2 short-course primaquine-only regimens
All patients made a full clinical recovery after treatment. One patient developed acute tonsillitis on day 5 but responded well to antibiotics (amoxicillin). His fever cleared 201 hours after starting primaquine treatment. The overall mean (SD) parasite clearance time was 87.7 hours (25.3 hours). The overall median (range) parasite reduction ratios at 24 hours and 48 hours were 2 (0.1–4.1) and 14.4 (0.1–1376), respectively. Between the 2 treatment groups, there were no significant differences in PCT or parasite reduction ratios (P ≥ 0.18). Excluding the patient with acute tonsillitis, the median fever clearance time was 47 hours (range 4 to 130 hours). On admission, 55 patients (64.7%) had gastrointestinal symptoms i.e. nausea (N = 36, 42.4%), vomiting (N = 14, 16.5%), abdominal pain (N = 14, 16.5%), and diarrhea (N = 3, 3.5%). These symptoms disappeared after day 3 in the majority of patients (N = 48/55; 87.3%) as the malaria infection subsided (). Only one patient who received daily 60 mg primaquine had persistent but mild abdominal pain till day 7 but this responded well to antacids. His pain resolved fully on the eighth day suggesting it was drug related. Transient localized rashes developed in 3 patients on day 0 to day 3 but all lasted only for 24 hours. Comparing the 2 treatment groups, the overall incidence of gastrointestinal symptoms during acute malaria (day 0–3) was significantly higher in the lower dose primaquine group (33/43 versus 22/44; P = 0.033). There was no other significant adverse effects or complications in the studied patients.
Proportions of patients with gastrointestinal symptoms during primaquine monotherapy for P. vivax malaria.
The mean ± SD baseline hematocrit of all patients (36.3% ± 5.6%) decreased significantly after day 2 to day 7 (, P < 0.001), then returned back to baseline values on day 14 (36.2% ± 3.7%; P = 0.07), and became significantly higher than the baseline hematocrit on day 28 (40.5% ± 3.6%, P = 0.001). The overall median hematocrit reduction was 8.8% (range 2.2–33.3%). A hematocrit drop of > 30% was observed in 2 cases; one from each group. The lowest recorded value was 30% on day 6 in one case and 28% on day 7 for the other. Neither was associated with symptoms and none of the studied patients needed a blood transfusion. Comparing the 2 treatment groups, there were no significant differences in the baseline hematocrit values (36.7 ± 5.9% versus 35.9 ± 5.3%; P = 0.50), the proportion of patients with hematocrit reduction (N = 40/43 versus 37/42; P = 0.34) or the magnitude of hematocrit reductions (, P ≥ 0.11).
Serial hematocrits (%) levels in adult G6PD normal patients treated with primaquine of 30 mg/day (open circles) or 60 mg/day (closed circles) for acute vivax malaria. Data are shown as mean (SD).
On admission, thrombocytopenia (platelets < 180,000/µL) was found in the majority of patients (87.8%; N = 72/82). The mean ± SD baseline platelet count was 111,000 ± 77,000/μL but then increased to above 200,000/μL in all subsequent follow-up assessments (day 7, day 14, and day 28) in both groups (). Except for the reduction in hematocrit and thrombocytopenia on admission, none of the studied patients showed significant persistent abnormal hematology findings during 1 month monitoring. An elevation of bilirubin > 3 mg/dL was found on admission only in 6 patients (4 group 1, 2 group 2) and in 2 was accompanied by SGPT elevation (52 and 64 Units/L). During the follow-up assessments, serum SGPT elevation of > 2-fold was found in 8 patients but all were transient and mild (maximum range = 84 to 199 Units/L). Except for one patient with a serum creatinine of 2.2 mg/dL on admission only, none of the studied patients had significant elevation of serum creatinine (> 2.0 mg/dL) throughout the follow-up period.
Laboratory findings in patients with P. vivax malaria on admission and follow-up
Plasmodium vivax gametocytemia.
During hospital stay, patent gametocytemia was detected in 62.4% (N = 53) of patients, 29.4% (N = 25) on admission and a further 32.9% (N = 28) after starting primaquine treatment. The gametocyte carriage of all studied patients (i.e., including those without gametocytemia) was brief; median was 12 hours (range, 0–74 hours) and was not significantly different between the two treatment groups (median 12; range 0–74 versus 7; 0–60 hours; P = 0.49). The overall gametocyte carriage rates were not significantly different between the 2 groups either before (N = 15 and 10) or after treatment (N = 14 and 14) (P = 0.58).
Gametocytemia before treatment and the ratio to asexual stage parasite densities were similar in the two treatment groups (). In patients with post-treatment gametocytemia, the 60 mg primaquine group showed slightly better suppression of gametocytemia compared with the 30 mg primaquine group with lower peak gametocyte/corresponding asexual parasite counts ratios (0.6% versus 3%, P = 0.016).
Relationship between sexual and asexual parasitemia in patients with P. vivax gametocytemia
Complete clinical and parasitological follow-up was obtained in 64 patients (75%). These patients were either followed-up outside the malaria transmission area for 28 days or remained in the hospital until the subsequent appearance of vivax or falciparum malaria. The remaining 25% of patients did not return after discharge. Their demographic and disease characteristics were similar to those successfully followed. There were no significant differences in proportion of loss to follow-up between the two treatment groups (12/43; 27.9% in the 30 mg groups versus 9/42; 21.4% in the 60 mg groups, P = 0.62).
Of the 31 patients successfully followed in the 30 mg group, 9 (29%) had reappearance of vivax and another one (3%) had emergence of falciparum malaria after a full clinical recovery and parasite clearance of the primary vivax illness. The corresponding figures were 2/33 (6%) relapses and 3 (7%) Plasmodium falciparum recrudescences in the 60 mg group. The incidence of vivax reappearance was significantly lower in the high dose primaquine group; by Kaplan Meier survival analysis with day 28 relapse estimates (95% Confidence interval) of 29% (16–49%) in the 30 mg group compared with 7% (2–24%) in the 60 mg group; P = 0.027 ().
Proportions of adult patients with recurrent P. vivax parasitemia in the 30 mg/day and 60 mg/day primaquine groups.
All patients with incomplete cure responded to retreatment with the corresponding standard regimens for vivax malaria or falciparum malaria. To assess these responses with primaquine monotherapy, we compared the results of the present study with the previously reported studies conducted in the same hospital (so reinfection could be excluded) and with similar patient groups with acute vivax malaria, in which primaquine (30 mg base or 60 mg base per day) was given together with artesunate (5 or 7 days) for 3, 5, or 7 days.5,7,8
Artesunate has no hypnozoitocidal activity but is highly effective against the blood stage infection. Recurrences after artesunate regimens are therefore assumed to be relapses (see Supplemental Appendix, available at www.ajtmh.org
). The 60 mg/day recurrence rates in this study are similar to those in the previous studies, which suggests first that this dose gives nearly maximal hypnozoitocidal activity, and second that the significantly higher recurrence rate with the 30 mg/day primaquine monotherapy results predominantly from recrudescences (Supplemental Appendix and ).
Figure 4. Recurrences following acute Plasmodium vivax malaria in adults studied in Thailand in a hospital setting for 28 days where reinfection was excluded. The horizontal axis shows the number of days for which primaquine was given. The open circles and bars (more ...)
Factors associated with gametocyte carriage.
The admission asexual parasite counts were not significantly different between patients with or without patent gametocytemia () that appeared either before or after treatment (P ≥ 0.11). Regardless of treatment groups, patients with gametocytemia cleared asexual parasite much slower that those without gametocytemia (P ≤ 0.018) and also had slower fever clearance times although this was not statistically significant (P = 0.075). This was not attributable to higher parasitemia as there were no significant differences in parasitemia between those with and without gametocytemia. There were also no significant differences in the numbers of previous malaria attacks, duration of fever, or admission hematocrit values or reappearance rate of vivax malaria between patients with and without gametocytemia ().
Comparison between patients with and without patent P. vivax gametocytemia