BackgroundPrimaquine is the only licensed drug for eradicating Plasmodium vivax hypnozoites and, therefore, preventing relapses of vivax malaria. It is a vital component of global malaria elimination efforts. Primaquine is efficacious when supervised in clinical trials, but its effectiveness in real-world settings is unknown. We aimed to determine whether unsupervised primaquine was effective for preventing re-presentation to hospital with vivax malaria in southern Papua, Indonesia.Methods and findingsRoutinely-collected hospital surveillance data were used to undertake a pragmatic comparison of the risk of re-presentation to hospital with vivax malaria in patients prescribed dihydroartemisinin-piperaquine (DHP) combined with primaquine versus those patients prescribed DHP alone. The omission of primaquine was predominantly due to 3 stock outages. Individual clinical, pharmacy, and laboratory data were merged using individual hospital identification numbers and the date of presentation to hospital. Between April 2004 and December 2013, there were 86,797 documented episodes of vivax malaria, of which 62,492 (72.0%) were included in the analysis. The risk of re-presentation with vivax malaria within 1 year was 33.8% (95% confidence Interval [CI] 33.1%–34.5%) after initial monoinfection with P. vivax and 29.2% (95% CI 28.1%–30.4%) after mixed-species infection. The risk of re-presentation with P. vivax malaria was higher in children 1 to <5 years of age (49.6% [95% CI 48.4%–50.9%]) compared to patients 15 years of age or older (24.2% [95% CI 23.4–24.9%]); Adjusted Hazard Ratio (AHR) = 2.23 (95% CI 2.15–2.31), p < 0.001. Overall, the risk of re-presentation was 37.2% (95% CI 35.6%–38.8%) in patients who were prescribed no primaquine compared to 31.6% (95% CI 30.9%–32.3%) in those prescribed either a low (≥1.5 mg/kg and <5 mg/kg) or high (≥5 mg/kg) dose of primaquine (AHR = 0.90 [95% CI 0.86–0.95, p < 0.001]). Limiting the comparison to high dose versus no primaquine in the period during and 12 months before and after a large stock outage resulted in minimal change in the estimated clinical effectiveness of primaquine (AHR 0.91, 95% CI 0.85–0.97, p = 0.003). Our pragmatic study avoided the clinical influences associated with prospective study involvement but was subject to attrition bias caused by passive follow-up.ConclusionsUnsupervised primaquine for vivax malaria, prescribed according to the current World Health Organization guidelines, was associated with a minimal reduction in the risk of clinical recurrence within 1 year in Papua, Indonesia. New strategies for the effective radical cure of vivax malaria are needed in resource-poor settings.
Artemisinin-resistant falciparum malaria, defined by a slow-clearance phenotype and the presence of kelch13 mutants, has emerged in the Greater Mekong Subregion. Naturally acquired immunity to malaria clears parasites independent of antimalarial drugs. We hypothesized that between-and within-population variations in host immunity influence parasite clearance after artemisinin treatment and the interpretation of emerging artemisinin resistance. Antibodies specific to 12 Plasmodium falciparum sporozoite and blood-stage antigens were determined in 959 patients (from 11 sites in Southeast Asia) participating in a multinational cohort study assessing parasite clearance half-life (PCt 1/2 ) after artesunate treatment and kelch13 mutations. Linear mixed-effects modeling of pooled individual patient data assessed the association between antibody responses and PCt 1/2. P. falciparum antibodies were lowest in areas where the prevalence of kelch13 mutations and slow PCt 1/2 were highest [Spearman ρ = −0.90 (95% confidence interval, −0.97, −0.65), and Spearman ρ = −0.94 (95% confidence interval, −0.98, −0.77), respectively]. P. falciparum antibodies were associated with faster PCt 1/2 (mean difference in PCt 1/2 according to seropositivity, −0.16 to −0.65 h, depending on antigen); antibodies have a greater effect on the clearance of kelch13 mutant compared with wild-type parasites (mean difference in PCt 1/2 according to seropositivity, −0.22 to −0.61 h faster in kelch13 mutants compared with wild-type parasites). Naturally acquired immunity accelerates the clearance of artemisininresistant parasites in patients with falciparum malaria and may confound the current working definition of artemisinin resistance. Immunity may also play an important role in the emergence and transmission potential of artemisinin-resistant parasites.malaria | artemisinin | drug resistance | immunity | serology
BackgroundOptimised two-dose human papillomavirus (HPV) vaccine schedules are now endorsed for young adolescents by the World Health Organization. Limited data are available about effectiveness of <3 doses using a standard dose schedule.MethodsDeterministic data linkage was undertaken between the Victorian Cervical Cytology Registry and National HPV Vaccination Program Register to determine quadrivalent HPV vaccination status and incidence of cervical pathology among vaccine eligible women (aged 26 years or younger in 2007) screened in Victoria, Australia between April 2007 and December 2011. Proportional hazards regression was used to estimate hazard ratios (HR) adjusted for age, socioeconomic status and area of residence. Women were stratified into those vaccinated before or after first screen.ResultsAny number of doses (1, 2 or 3) were associated with lower rates of high grade and low grade cytology diagnoses as long as doses were given before screening commencement (one dose HR high grade 0.44 (95% CI 0.32–0.59), one dose low grade 0.48 (95% CI 0.40–0.58); two doses HR high grade 0.63 (95% CI 0.50–0.80), HR low grade 0.52 (95% CI 0.44–0.61); three doses HR high grade 0.53 (95% CI 0.47–0.60), HR low grade 0.73 (95% CI 0.68–0.78)). Three doses of vaccine, but not fewer, were associated with reduced risk of high grade histologically confirmed abnormality in this cohort, regardless of whether vaccination occurred before or after screening (HR before 0.71 (95% CI 0.64–0.80), HR after 0.87 (95% CI 0.82–0.93)). Secondary analyses censoring end points occurring within 1, 6, 12, or 24 months of final vaccine dose suggested an increasing effect of partial vaccination courses over time.ConclusionOur data suggest that less than three doses of quadrivalent HPV vaccine provides some protection against cervical intraepithelial neoplasia, even when measured within 5 years in a population including those who were sexually active at the time of vaccination.
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