Safety of single low-dose primaquine in glucose-6-phosphate dehydrogenase deficient falciparum-infected African males: Two open-label, randomized, safety trials.

BACKGROUND: Primaquine (PQ) actively clears mature Plasmodium falciparum gametocytes but in glucose-6-phosphate dehydrogenase deficient (G6PDd) individuals can cause hemolysis. We assessed the safety of low-dose PQ in combination with artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) in G6PDd African males with asymptomatic P. falciparum malaria. METHODS AND FINDINGS: In Burkina Faso, G6PDd adult males were randomized to treatment with AL alone (n = 10) or with PQ at 0.25 (n = 20) or 0.40 mg/kg (n = 20) dosage; G6PD-normal males received AL plus 0.25 (n = 10) or 0.40 mg/kg (n = 10) PQ. In The Gambia, G6PDd adult males and boys received DP alone (n = 10) or with 0.25 mg/kg PQ (n = 20); G6PD-normal males received DP plus 0.25 (n = 10) or 0.40 mg/kg (n = 10) PQ. The primary study endpoint was change in hemoglobin concentration during the 28-day follow-up. Cytochrome P-450 isoenzyme 2D6 (CYP2D6) metabolizer status, gametocyte carriage, haptoglobin, lactate dehydrogenase levels and reticulocyte counts were also determined. In Burkina Faso, the mean maximum absolute change in hemoglobin was -2.13 g/dL (95% confidence interval [CI], -2.78, -1.49) in G6PDd individuals randomized to 0.25 PQ mg/kg and -2.29 g/dL (95% CI, -2.79, -1.79) in those receiving 0.40 PQ mg/kg. In The Gambia, the mean maximum absolute change in hemoglobin concentration was -1.83 g/dL (95% CI, -2.19, -1.47) in G6PDd individuals receiving 0.25 PQ mg/kg. After adjustment for baseline concentrations, hemoglobin reductions in G6PDd individuals in Burkina Faso were more pronounced compared to those in G6PD-normal individuals receiving the same PQ doses (P = 0.062 and P = 0.022, respectively). Hemoglobin levels normalized during follow-up. Abnormal haptoglobin and lactate dehydrogenase levels provided additional evidence of mild transient hemolysis post-PQ. CONCLUSIONS: Single low-dose PQ in combination with AL and DP was associated with mild and transient reductions in hemoglobin. None of the study participants developed moderate or severe anemia; there were no severe adverse events. This indicates that single low-dose PQ is safe in G6PDd African males when used with artemisinin-based combination therapy. TRIAL REGISTRATION: Clinicaltrials.gov NCT02174900 Clinicaltrials.gov NCT02654730

Scale-up of Malaria Rapid Diagnostic Tests and Artemisinin-Based Combination Therapy: Challenges and Perspectives in Sub-Saharan Africa.

Guido Bastiaens and colleagues describe barriers to achieving scale-up and appropriate use of rapid diagnostic tests and artemisinin-based combination therapy for malaria in sub-Saharan Africa. Please see later in the article for the Editors' Summary

Efficacy of Single-Dose Primaquine With Artemisinin Combination Therapy on Plasmodium falciparum Gametocytes and Transmission: An Individual Patient Meta-Analysis

Background Since the World Health Organization recommended single low-dose (0.25mg/kg) primaquine (PQ) in combination with artemisinin-based combination therapies (ACTs) in areas of low transmission or artemisinin-resistant P. falciparum, several single-site studies have been conducted to assess its efficacy. Methods An individual patient meta-analysis to assess the gametocytocidal and transmission-blocking efficacy of PQ used in combination with different ACTs was conducted. Random effects logistic regression was used to quantify PQ effect on (i) gametocyte carriage in the first two weeks post-treatment; (ii) the probability of infecting at least one mosquito or of a mosquito becoming infected. Results In 2,574 participants from fourteen studies, PQ reduced PCR-determined gametocyte carriage on days 7 and 14, most apparently in patients presenting with gametocytaemia on day 0 (Odds Ratio (OR)=0.22; 95%CI 0.17-0.28 and OR=0.12; 95%CI 0.08–0.16, respectively). The rate of decline in gametocyte carriage was faster when PQ was combined with artemether-lumefantrine (AL) compared to dihydroartemisinin-piperaquine (DP) (p=0.010 for day 7). Addition of 0.25mg/kg PQ was associated with near complete prevention of transmission to mosquitoes. Conclusion Primaquine’s transmission-blocking effects are achieved with 0.25 mg/kg PQ. Gametocyte persistence and infectivity are lower when PQ is combined with AL compared to DP

Nosocomial outbreak of multi-resistant Streptococcus pneumoniae serotype 15A in a centre for chronic pulmonary diseases

Abstract We report nosocomial transmission of multi-resistant serotype 15A Streptococcus pneumoniae (MRSP) that resulted in two lower respiratory tract infections in a centre for chronic pulmonary diseases. This outbreak highlights the potential for transmission of MRSP among vulnerable patients when laboratory turnaround time is long and patient compliance with transmission-based precautions is low

Parasitemia during CPS immunization.

<p>Parasitemia was determined retrospectively, once daily from day 6 until day 10 after each immunization, by real-time quantitative PCR (qPCR). Each line represents an individual subject from the CPS-MQ (dashed blue lines) or CPS-CQ group (red lines). The number of subjects with a positive qPCR/total number of volunteers in the CPS-MQ (blue) and CPS-CQ (red) groups after each immunization are shown above the graph. Values shown as 17.5 on the log-scale were negative (i.e. half the detection limit of the qPCR: 35 parasites/ml).</p

Parasitemia after challenge infection.

<p>Parasitemia was assessed retrospectively by real-time quantitative PCR (qPCR) twice daily from day 5 until day 15 and once daily up until day 21 after challenge. Each line represents an individual subject. Red lines represent CPS-CQ immunized volunteers (n = 5), dashed blue lines CPS-MQ immunized subjects (n = 10) and dotted grey lines malaria-naive control subjects (n = 4). Values shown as 17.5 on the log-scale were negative (i.e. half the detection limit of the qPCR: 35 parasites/ml).</p

Cellular immune responses: CD107a expression by CD4 T cells and granzyme B production by CD8 T cells.

<p>CD107a expression by CD4 T cells after <i>Pf</i>RBC re-stimulation, corrected for uRBC background in CPS-CQ (A) and CPS-MQ (B) groups; granzyme B production by CD8 T cells after <i>Pf</i>RBC re-stimulation, corrected for uRBC background in CPS-CQ (C) and CPS-MQ (D) groups. Symbols and lines represent individual subjects before immunization (B) and one day before challenge (C-1). Open squares indicate protected subjects, filled circles indicate unprotected subjects. Differences between B and C-1 for all subjects were tested by Wilcoxon matched-pairs signed rank test.</p

Protection against challenge infection after CPS-CQ and CPS-MQ immunization.

a<p>Presented as protected/total number of subjects.</p>b<p>Presented as % protected (95% CI by modified Wald Method).</p>c<p>Presented as median (range) days.</p>d,e<p>p-value calculated by Fisher’s exact test comparing ^dCPS-MQ versus CPS-CQ or ^econtrol versus all CPS-immunized subjects.</p>f,g<p>p-value calculated by Mann Whitney test comparing ^fCPS-MQ versus CPS-CQ or ^gcontrol versus all CPS-immunized subjects (both excluding protected subjects).</p><p>Protection against challenge infection after CPS-CQ and CPS-MQ immunization.</p

Antibody responses induced by CPS-CQ and CPS-MQ immunization.

<p>Antibodies against CSP (A and B; in AU), LSA-1 (C and D), and MSP-1 (E and F) were analyzed at baseline (B), 28 days after the first (I1) and second (I2) immunization and one day before challenge (C-1; 20 weeks after the last immunization) for all CPS-CQ (A, C and E, n = 5) and CPS-MQ (B, D and F, n = 10) immunized volunteers. Data are shown as individual titers with medians. Open squares indicate protected subjects, filled circles indicate unprotected subjects. Differences between the time points were analyzed by Friedman test with Dunn’s multiple comparison post-hoc test. Significant differences are indicated by asterices with * (p<0.05), ** (p<0.01), *** (p<0.001).</p