AS or ACT partner treatments (comparison 5)
Microscopy analysis revealed that PQ clearly reduced the number of people infected with gametocytes (Analysis 5.1), on day 8 (RR 0.15, 95% CI 0.09 to 0.24, four trials, eight comparisons), day 15 (RR 0.10, 95% CI 0.04 to 0.22, three trials, seven comparisons), day 22 (RR 0.06, 95% CI 0.01 to 0.24, two trials, six comparisons, three with estimable results) and day 29 (RR 0.15, 95% CI 0.05 to 0.51, three trials, seven comparisons, three with estimable results). In Smithuis 2010, new gametocytaemia (by microscopy) on day 7 was also reduced by PQ (one of 272 versus 10 of 268; RR 0.1, 95% CI 0.01 to 0.76, P = 0.006).
Two trials examined gametocytes by PCR rather than microscopy. In one trial (Shekalaghe 2007), a reduction in gametocyte prevalence was observed on day 8 and day 15 (Analysis 5.2). However, in the other trial (El-Sayed 2007), giving PQ did not lead to a detectable difference between the two groups on these two follow-up days, although there were very few participants with gametocytes in the control group. Given the clear statistical and clinical heterogeneity between the two estimates (related to different numbers of participants with gametocytes in the comparator arm in these two studies) we did not combine them in meta-analysis Analysis 5.2. In Shekalaghe 2007, with additional follow-up day 29, reduction in gametocyte prevalence was significant (RR 0.23, 95% CI 0.08 to 0.62), and on day 43, it was not (Analysis 5.2).
Gametocyte density over time was assessed by microscopy in the trials of Shekalaghe 2007, Smithuis 2010 (five comparisons) and Vasquez 2009, and is analysed further below using the AUC measure estimated from data provided by the authors. For PCR detected gametocyte density, Shekalaghe 2007 provided geometric mean and inter-quartile range (IQR) on days 1, 4, 8, 15, 29 and 43, and mean density was consistently lower in the PQ than the non-group, for days when gametocytes were detected (with PQ: 5.8, IQR 0.8 to 55.1; without PQ: 15.8, IQR 4.1 to 85.8).
Gametocyte clearance time is presented in Shekalaghe 2007 and was significantly lower in the PQ group (6.3 days, 95% CI 4.7 to 8.5) than in the non-PQ group (28.6 days, 95% CI 17.0 to 48.0, P < 0.001). Smithuis 2010 also reported significantly lower gametocyte clearance time in the PQ groups, reported as person gametocytaemia weeks standardized per 1000 person-weeks of follow-up. This was 5.5 weeks in the ACT+PQ groups versus 65.5 weeks in the non-PQ groups (RR 11.9, 95% CI 7.4 to 20.5, P < 0.001) and the difference was very large for each individual partner drug. Although the duration of gametocyte carriage (without PQ) was significantly longer for AS+AQ, AL and DHAP than for AS+MQ, there was no significant difference in length of gametocyte carriage between the ACT groups when PQ was added (Smithuis 2010).
Shekalaghe 2007 was the only trial to present a comparison of AUC of gametocyte density (by PCR) over time, with a 95% CI derived from generalized estimation equations. Shekalaghe 2007 derived AUC from gametocyte densities estimated on days 1, 4, 8, 15, 29 and 43 (reported in trial as days 0, 3, 7, 14, 28 and 42). There was a significant reduction in AUC in the PQ groups over 43 days after treatment, reported as mean of 1.5 (IQR 0.3 to 8.8) in the PQ group versus 11.1 (IQR 2.2 to 53.8) in the non-PQ group (P < 0.001). We used trial raw data to estimate geometric mean and SD for this variable (Analysis 5.3) and observed a significant reduction in AUC (expressed as log(10)) with a mean difference of -0.88 [-1.32, -0.43].
There was no difference between PQ and non-PQ groups in proportion of participants with asexual parasites (Analysis 5.4) or asexual parasite clearance time (Analysis 5.5). No difference in asexual recrudescence rates was noted in Smithuis 2010.
For haematologic adverse events, Smithuis 2010 stated that there were no cases of severe anaemia (<5g/dL) or blackwater fever in any group. El-Sayed 2007 showed that there was no difference in packed cell volume between groups at day 7 (34.2% (15 to 44%) versus 36.2% (26 to 42%)) or day 14 (35.2% versus 35.4%). The difference was not significant at either day 7 (0.78, (-0.75 to 0.23) P = 0.32) or day 14 (0.86, (-0.31 to +2.0) P = 0.15). In Shekalaghe 2007, although there was also no reduction in mean haemoglobin by group (Analysis 5.6), there was a significantly greater change (decrease) in haemoglobin status in the PQ group on day 8; haemoglobin decreased by 5% in the PQ group compared to 1% in the non-PQ group (Analysis 5.7). These findings suggest that rather than look at population mean of haemoglobin, it would be more meaningful to examine the proportion of individuals who had serious adverse events: Shekalaghe 2007 state that 8 of 52 children in the PQ group had 20% reduction in haemoglobin by day 8, compared to 0 of 53 children in the control group. However, it is also stated that no child developed clinical symptoms related to anaemia or a haemoglobin below 5 g/dL. The effect on haemoglobin in the PQ group was transient and was no longer significant by day 15.
El-Sayed 2007 assessed he minor adverse effects of vomiting, insomnia and itching and found no difference between groups. Smithuis 2010 found a higher percentage of patients in the PQ groups had abdominal pain (16%; N = 397 versus 11%; N = 411, P = 0.05); frequencies of dizziness, nausea, anorexia, diarrhoea, palpitations, sleeplessness, headache and vomiting were not increased in the PQ groups.