Artemether-Lumefantrine versus Dihydroartemisinin-Piperaquine for Treatment of Uncomplicated Plasmodium falciparum Malaria in Children Aged Less than 15 Years in Guinea-Bissau - An Open-Label Non-Inferiority Randomised Clinical Trial

Background Artemether-lumefantrine (AL) was introduced for treatment of uncomplicated malaria in Guinea-Bissau in 2008. Malaria then resurged and recurrent malaria after treatment with AL and stock-outs of AL were common. This study therefore aimed to assess the efficacy of AL and identify an alternative second line antimalarial. Dihydroartemisinin-piperaquine (DP) was chosen as it has been shown to be safe and efficacious and to reduce the incidence of recurrent malaria. Methods and Findings In a multicentre randomised open-label non-inferiority clinical trial, AL or DP were given over 3 days to children aged 6 months-15 years with uncomplicated P. falciparummonoinfection. Intake was observed and AL was given with milk. Children were seen on days 0, 1, 2 and 3 and then weekly days 7-42. Recurring P. falciparumwere classified as recrudescence or new infections by genotyping. Between November 2012 and July 2015, 312 children were randomised to AL (n = 155) or DP (n = 157). The day 42 PCR adjusted per protocol adequate clinical and parasitological responses were 95% and 100% in the AL and DP groups respectively, Mantel-Haenszel weighted odds ratio (OR) 0.22 (95% CI 0-0.68), p = 0.022. In a modified intention to treat analysis in which treatment failures day 0 and reinfections were also considered as treatment failures adequate clinical and parasitological responses were 94% and 97% (OR 0.42 [95% CI, 0.13-1.38], p = 0.15). Parasite clearance and symptom resolution were similar with both treatments. Conclusions Both treatments achieved the WHO recommended efficacy for antimalarials about to be adopted as policy. DP was not inferior to AL for treatment of uncomplicated P. falciparum malaria in Guinea-Bissau

The Introduction of Diphtheria-Tetanus-Pertussis and Oral Polio Vaccine Among Young Infants in an Urban African Community:A Natural Experiment

Background: We examined the introduction of diphtheria-tetanus-pertussis (DTP) and oral polio vaccine (OPV) in an urban community in Guinea-Bissau in the early 1980s. Methods: The child population had been followed with 3-monthly nutritional weighing sessions since 1978. From June 1981 DTP and OPV were offered from 3 months of age at these sessions. Due to the 3-monthly intervals between sessions, the children were allocated by birthday in a ‘natural experiment’ to receive vaccinations early or late between 3 and 5 months of age. We included children who were <6 months of age when vaccinations started and children born until the end of December 1983. We compared mortality between 3 and 5 months of age of DTP-vaccinated and not-yet-DTP-vaccinated children in Cox proportional hazard models. Results: Among 3–5-month-old children, having received DTP (±OPV) was associated with a mortality hazard ratio (HR) of 5.00 (95% CI 1.53–16.3) compared with not-yet-DTP-vaccinated children. Differences in background factors did not explain the effect. The negative effect was particularly strong for children who had received DTP-only and no OPV (HR = 10.0 (2.61–38.6)). All-cause infant mortality after 3 months of age increased after the introduction of these vaccines (HR = 2.12 (1.07–4.19)). Conclusion: DTP was associated with increased mortality; OPV may modify the effect of DTP

Which children come to the health centre for treatment of malaria?

Malaria remains one of the major public health problems for children in Guinea-Bissau and the major reason for using the health services. Little is known about factors with impact on whether the mothers seek malaria treatment for their children at a health centre. Mothers of children coming to the Bandim Health Centre in Bissau and age-matched controls selected from the registration system of the Bandim Health Project were interviewed about treatment habits, socio-economic standards and other factors associated with the mother seeking treatment for her child at a health centre. In a multivariate analysis, the controls were more often found to have chloroquine at home and had more often taken home treatment for suspected malaria. On average 2.97 persons among cases shared bed as opposed to only 2.02 among controls, bed-crowding thus, being a factor determining health seeking behaviour (P=0.0001). Low socio-economic status, as measured by the non-availability of electricity, was also a significant predicting factor (P=0.02). The possibilities of promoting home treatment should be further evaluated, not only to avoid unnecessary visits to the professional health system, but also to decrease the morbidity from acute malaria

Oral polio vaccination and low case fatality at the paediatric ward in Bissau, Guinea-Bissau.

Oral polio vaccine (OPV) and diphtheria-tetanus-pertussis (DTP) vaccines are given simultaneously in routine immunisation programmes in developing countries. It is therefore difficult to determine the separate effects of these vaccines on survival. We used the shortage of DTP vaccine in Bissau to examine the impact of OPV on the case fatality at the paediatric ward in Bissau. For 719 children less than 5 years of age whose vaccination card had been seen at admission and who had not yet received measles vaccine, having received OPV only was associated with a case fatality of 6% compared with 15% for children having received combined DTP and OPV vaccinations, the case fatality ratio (CFR) being 0.29 (95% confidence interval (CI) 0.11-0.77). Even if children fleeing the hospital were assumed to have died shortly after leaving the hospital, the case fatality would still be lower for children having received OPV only (CFR = 0.41; (95% CI 0.20-0.81)). The tendency was similar for children hospitalised with pneumonia, diarrhoea, and presumptive malaria. Control for background factors had no impact on the estimate. In areas with high mortality, OPV administered alone may have non-specific beneficial effects or DTP may have a negative effect for children who had received both DTP and OPV

Eff ects of the introduction of new vaccines in Guinea-Bissau on vaccine coverage, vaccine timeliness, and child survival:an observational study

Background In 2008, the GAVI Alliance funded the introduction of new vaccines (including pentavalent diphtheriatetanus- pertussis [DTP] plus hepatitis B and Haemophilus infl uenzae type b antigens) in Guinea-Bissau. The introduction was accompanied by increased vaccination outreach services and a more restrictive wastage policy, including only vaccinating children younger than 12 months. We assessed coverage of all vaccines in the Expanded Program on Immunizations before and after the new vaccines’ introduction, and the implications on child survival. Methods This observational cohort study used data from the Bandim Health Project, which has monitored vaccination status and mortality in randomly selected village clusters in Guinea-Bissau since 1990. We assessed the change in vaccination coverage using cohort data from children born in 2007 and 2009; analysed the proportion of children who received measles vaccine after 12 months of age using data from 1999–2006; and compared child mortality after age 12 months in children who had received measles vaccine and those who had not using data from 1999 to 2006. Findings The proportion of children who were fully vaccinated by 12 months of age was 53% (468 of 878) in the 2007 cohort and 53% (467 of 879) in the 2009 cohort (relative risk [RR] 1·00, 95% CI 0·89–1·11). Coverage of DTP-3 and pentavalent-3 increased from 73% (644 of 878) in 2007 to 81% (712 of 879) in 2009 (RR 1·10, 95% CI 1·04 –1·17); by contrast, the coverage of measles vaccination declined from 71% (620 of 878) to 66% (577 of 879; RR 0·93, 0·85–1·01). The eff ect of the changes was signifi cantly diff erent for DTP-3 coverage compared with measles vaccine coverage (p=0·002). After 12 months of age, the adjusted mortality rate ratio was 0·71 (95% CI 0·56–0·90) for children who had received measles vaccine compared with those who had not (0·59 [0·43–0·80] for girls and 0·87 [0·62–1·23] for boys). Interpretation The introduction of the new vaccination programme in 2008 was associated with increased coverage of DTP, but decreased coverage of measles vaccine. In 1999–2006, child mortality was higher in children who had not received measles vaccine than in those who had

Does oral polio vaccine have non-specific effects on all-cause mortality? Natural experiments within a randomised controlled trial of early measles vaccine.

BACKGROUND: BCG and measles vaccine (MV) may have beneficial non-specific effects (NSEs). If an unplanned intervention with a vaccine (a natural experiment) modifies the estimated effect in a randomised controlled trial (RCT), this suggests NSEs. We used this approach to test NSEs of triple oral polio vaccine (OPV). METHODS: During an RCT of 2 doses of MV at 4.5 and 9 months versus 1 dose of MV at 9 months of age, we experienced 2 natural experiments with OPV. We assessed whether these OPV experiments modified the effect of 2-dose MV in the MV trial. SETTING: MV RCT conducted in urban Guinea-Bissau 2003-2009. INTERVENTIONS: Natural experiments with OPV due to missing vaccine and the implementation of OPV campaigns. MAIN OUTCOME MEASURE: Changes in the mortality rate ratio (MRR) for 2-dose MV versus 1-dose MV. RESULTS: First, the MRR (2-dose/1-dose MV) overall was 0.70 (0.52 to 0.94), but the MRR was 1.04 (0.53 to 2.04) when OPV at birth (OPV0) was not given, suggesting that early priming with OPV was important for the effect of 2-dose MV. The effect of OPV0 depended on age of administration; the MRR (2-dose/1-dose MV) was 0.45 (0.29 to 0.71) for children receiving OPV0 in the first week of life, but 3.63 (0.87 to 15.2) for those receiving OPV0 after the first month of life (p=0.007, test of no interaction). Second, campaign-OPV may have reduced the difference between the randomisation groups since the MRR (2-dose/1-dose MV) was 0.60 (0.42 to 0.85) for children who had not received campaign-OPV before RCT-enrolment versus 0.72 (0.23 to 2.31) and 1.42 (0.70 to 2.90) for children who had received 1 or 2 doses of campaign-OPV-before-enrolment, respectively. CONCLUSIONS: Bissau had no polio infection during this trial, so OPV0 and campaign-OPV may have NSEs since they modified the effect of 2-dose MV in an RCT. Different interventions may interact to a much larger effect than usually assumed

Sex-Differential Effect on Infant Mortality of Oral Polio Vaccine Administered with BCG at Birth in Guinea-Bissau. A Natural Experiment

The policy to provide oral polio vaccine (OPV) at birth was introduced in low-income countries to increase coverage. The effect of OPV at birth on overall child mortality was never studied. During a trial of vitamin A supplementation (VAS) at birth in Guinea-Bissau, OPV was not available during several periods. We took advantage of this "natural experiment" to test the effect on mortality of receiving OPV at birth.Between 2002 and 2004, the VAS trial randomised normal-birth-weight infants to 50,000 IU VAS or placebo administered with BCG. Provision of OPV at birth was not part of the trial, but we noted whether the infants received OPV or not. OPV was missing during several periods in 2004. We used Cox proportional hazards models to compute mortality rate ratios (MRR) of children who had received or not received OPV at birth.A total of 962 (22.1%) of the 4345 enrolled children did not receive OPV at birth; 179 children died within the first year of life. Missing OPV at birth was associated with a tendency for decreased mortality (adjusted MRR = 0.69 (95% CI = 0.46-1.03)), the effect being similar among recipients of VAS and placebo. There was a highly significant interaction between OPV at birth and sex (p = 0.006). Not receiving OPV at birth was associated with a weak tendency for increased mortality in girls (1.14 (0.70-1.89)) but significantly decreased mortality in boys (0.35 (0.18-0.71)).In our study OPV at birth had a sex-differential effect on mortality. Poliovirus is almost eradicated and OPV at birth contributes little to herd immunity. A randomised study of the effect of OPV at birth on overall mortality in both sexes is warranted

The Effect of 50 000 IU Vitamin A with BCG Vaccine at Birth on Growth in the First Year of Life

Vitamin A supplements may interact with diphtheria-tetanus-pertussis (DTP) vaccine causing increased female mortality. In a randomised trial of neonatal vitamin A supplementation (VAS), we examined growth during the first year of life in 808 children, pursuing the hypothesis that a negative interaction between VAS and DTP in girls would be reflected in growth. Length and weight were measured at 6 weekly visits and WHO-growth-reference z-scores derived. Neonatal VAS had no effect on anthropometric measures at 12 months, but may interact sex differentially with routine vaccines. While BCG was the most recent vaccine, neonatal VAS benefitted growth (difference in weight-for-length z-score (dWFL: 0.31(95% CI: 0.03–0.59)). While DTP was the most recent vaccine, VAS tended to affect growth adversely in girls (dWFL = −0.21 (−0.48–0.06)). After measles vaccine (MV) there was no overall effect of neonatal VAS. The VAS effect differed significantly between the BCG and DTP windows (P = 0.03), and the difference was borderline significant between the DTP and MV windows for girls (P = 0.09)