Key issues in the persistence of poliomyelitis in Nigeria: a case-control study

Background The completion of poliomyelitis eradication is a global emergency for public health. In 2012, more than 50% of the world’s cases occurred in Nigeria following an unanticipated surge in incidence. We aimed to quantitatively analyse the key factors sustaining transmission of poliomyelitis in Nigeria and to calculate clinical effi cacy estimates for the oral poliovirus vaccines (OPV) currently in use. Methods We used acute fl accid paralysis (AFP) surveillance data from Nigeria collected between January, 2001, and December, 2012, to estimate the clinical effi cacies of all four OPVs in use and combined this with vaccination coverage to estimate the eff ect of the introduction of monovalent and bivalent OPV on vaccine-induced serotype-specifi c population immunity. Vaccine effi cacy was determined using a case-control study with CIs based on bootstrap resampling. Vaccine effi cacy was also estimated separately for north and south Nigeria, by age of the children, and by year. Detailed 60-day follow-up data were collected from children with confi rmed poliomyelitis and were used to assess correlates of vaccine status. We also quantitatively assessed the epidemiology of poliomyelitis and programme performance and considered the reasons for the high vaccine refusal rate along with risk factors for a given local government area reporting a case. Findings Against serotype 1, both monovalent OPV (median 32·1%, 95% CI 26·1–38·1) and bivalent OPV (29·5%, 20·1–38·4) had higher clinical effi cacy than trivalent OPV (19·4%, 16·1–22·8). Corresponding data for serotype 3 were 43·2% (23·1–61·1) and 23·8% (5·3–44·9) compared with 18·0% (14·1–22·1). Combined with increases in coverage, this factor has boosted population immunity in children younger than age 36 months to a record high (64–69% against serotypes 1 and 3). Vaccine effi cacy in northern states was estimated to be signifi cantly lower than in southern states (p≤0·05). The proportion of cases refusing vaccination decreased from 37–72% in 2008 to 21–51% in 2012 for routine and supplementary immunisation, and most caregivers cited ignorance of either vaccine importance or availability as the main reason for missing routine vaccinations (32·1% and 29·6% of cases, respectively). Multiple regression analyses highlighted associations between the age of the mother, availability of OPV at health facilities, and the primary source of health information and the probability of receiving OPV (all p<0·05). Interpretation Although high refusal rates, low OPV campaign awareness, and heterogeneous population immunity continued to support poliomyelitis transmission in Nigeria at the end of 2012, overall population immunity had improved due to new OPV formulations and improvements in programme delivery.Funding Bill & Melinda Gates Foundation Vaccine Modeling Initiative, Royal Society.Introduction In May, 2012, after more than 20 years of mass vaccination campaigns, the 65t

Effect of trimethoprim-sulphamethoxazole on the risk of malaria in HIV-infected Ugandan children living in an area of widespread antifolate resistance

<p>Abstract</p> <p>Background</p> <p>Daily trimethoprim-sulfamethoxazole (TS) protects against malaria, but efficacy may be diminished as anti-folate resistance increases. This study assessed the incidence of falciparum malaria and the prevalence of resistance-conferring <it>Plasmodium falciparum </it>mutations in HIV-infected children receiving daily TS and HIV-uninfected children not taking TS.</p> <p>Materials and methods</p> <p>Subjects were 292 HIV-infected and 517 uninfected children from two cohort studies in Kampala, Uganda observed from August 2006 to December 2008. Daily TS was given to HIV-infected, but not HIV-uninfected children and all participants were provided an insecticide-treated bed net. Standardized protocols were used to measure the incidence of malaria and identify markers of antifolate resistance.</p> <p>Results</p> <p>Sixty-five episodes of falciparum malaria occurred in HIV-infected and 491 episodes in uninfected children during the observation period. TS was associated with a protective efficacy of 80% (0.10 vs. 0.45 episodes per person year, p < 0.001), and efficacy did not vary over three consecutive 9.5 month periods (81%, 74%, 80% respectively, p = 0.506). The prevalences of <it>dhfr </it>51I, 108N, and 59R and <it>dhps </it>437G and 540E mutations were each over 90% among parasites infecting both HIV-infected and uninfected children. Prevalence of the <it>dhfr </it>164L mutation, which is associated with high-level resistance, was significantly higher in parasites from HIV-infected compared to uninfected children (8% vs. 1%, p = 0.001). Sequencing of the <it>dhfr </it>and <it>dhps </it>genes identified only one additional polymorphism, <it>dhps </it>581G, in 2 of 30 samples from HIV-infected and 0 of 54 samples from uninfected children.</p> <p>Conclusion</p> <p>Despite high prevalence of known anti-folate resistance-mediating mutations, TS prophylaxis was highly effective against malaria, but was associated with presence of <it>dhfr </it>164L mutation.</p

Comparing changes in haematologic parameters occurring in patients included in randomized controlled trials of artesunate-amodiaquine vs single and combination treatments of uncomplicated falciparum in sub-Saharan Africa

<p>Abstract</p> <p>Background</p> <p>Artesunate-amodiaquine (AS&AQ) is a widely used artemisinin combination therapy (ACT) for falciparum malaria. A comprehensive appreciation of its effects on haematology <it>vs </it>other anti-malarials is needed in view of potential safety liabilities.</p> <p>Methods</p> <p>Individual-patient data analysis conducted on a database from seven randomized controlled trials conducted in sub-Saharan African comparing AS&AQ to reference treatments in uncomplicated falciparum malaria patients of all ages. Haematologic values (white cells total and neutrophil counts, haemoglobin/haematocrit, platelets) were analysed as both continuous and categorical variables for their occurrence, (severity grade 1-4) and changes during follow-up. Risks and trends were calculated using multivariate logistic random effect models.</p> <p>Results</p> <p>4,502 patients (72% < 5 years old), from 13 sites in nine countries with 28-day follow-up were treated with AS&AQ (45%) or a comparator (other forms of ACT accounted for 27%, other combination 12%, mono-therapies 16%). Pre-treatment leucopaenia (3%) and neutropaenia (6%) were infrequent; anaemia was common (39%). The treatment-emergent adverse events incidence (TEAE = condition not present or less severe pre-treatment) was 11% for neutropaenia, 6% for thrombocytopaenia with AS&AQ and not different from treatment groups; anaemia was higher with AS&AQ (20%) or other forms of ACT (22%) than in non-artemisinin groups (4%, <it>p </it>= 0.001). Multivariate analysis showed that the risk of anaemia, thrombocytopaenia, and leucopaenia decreased with follow-up time, while neutropaenia increased; the risk of anaemia and thrombocytopaenia increased with higher baseline parasitaemia and parasitological reappearance. White cells total count was not a good surrogate for neutropaenia. No systematic significant difference between treatments was detected. Older patients were at lower risks.</p> <p>Conclusion</p> <p>The effects of AS&AQ on haematologic parameters were not different from those of other anti-malarial treatments used in sub-Saharan Africa. This analysis provides the basis for a broader evaluation of haematology following anti-malarial treatment. Continuing monitoring of haematologic safety on larger databases is required.</p

Human immunodeficiency virus infection and cerebral malaria in children in Uganda: a case-control study

<p>Abstract</p> <p>Background</p> <p>Human immunodeficiency virus (HIV)-1 infection increases the burden of malaria by increasing susceptibility to infection and decreasing the response to malarial treatment. HIV-1 has also been found to suppress the immune system and predispose to severe forms of malaria in adults. There is still a paucity of data on the association between HIV-1 infection and cerebral malaria in children. The aim of this study was to determine whether HIV-1 infection is a risk factor for cerebral malaria in children.</p> <p>Method</p> <p>We conducted an unmatched case-control study, in which 100 children with cerebral malaria were compared with 132 with uncomplicated malaria and 120 with no malaria. In stratified analyses we estimated odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for age.</p> <p>Results</p> <p>HIV-1 infection was present in 9% of children with cerebral malaria compared to 2.3% in uncomplicated malaria (age-adjusted odds ratio (aOR) 5.94 (95% confidence interval (CI) 1.36-25.94, p = 0.012); and 2.5% in children with no malaria (aOR 3.85 (95% CI0.99-14.93, p = 0.037). The age-adjusted odds of being HIV-positive among children with cerebral malaria compared to the control groups (children with uncomplicated malaria and no malaria) was 4.98 (95% CI 1.54-16.07), p-value = 0.003.</p> <p>Conclusions</p> <p>HIV-1 infection is associated with clinical presentation of cerebral malaria in children. Clinicians should ensure that children diagnosed with HIV infection are initiated on cotrimoxazole prophylaxis as soon as the diagnosis is made and caretakers counselled on the importance of adherence to the cotrimoxazole towards reducing the risk of acquiring <it>P.falciparum </it>malaria and associated complications such as cerebral malaria. Other malaria preventive measures such as use of insecticide-treated mosquito nets should also be emphasized during counselling sessions.</p

Combined chloroquine, sulfadoxine/pyrimethamine and primaquine against Plasmodium falciparum in Central Java, Indonesia

BACKGROUND: Chloroquine (CQ) or sulfadoxine-pyrimethamine (SP) monotherapy for Plasmodium falciparum often leads to therapeutic failure in Indonesia. Combining CQ with other drugs, like SP, may provide an affordable, available and effective option where artemisinin-combined therapies (ACT) are not licensed or are unavailable. METHODS: This study compared CQ (n = 29 subjects) versus CQ + SP (with or without primaquine; n = 88) for clinical and parasitological cure of uncomplicated falciparum malaria in the Menoreh Hills region of southern Central Java, Indonesia. Gametocyte clearance rates were measured with (n = 56 subjects) and without (n = 61) a single 45 mg dose of primaquine (PQ). RESULTS: After 28 days, 58% of subjects receiving CQ had cleared parasitaemia and remained aparasitaemic, compared to 94% receiving CQ combined with SP (p < 0.001). Msp-2 genotyping permitted reinfection-adjusted cure rates for CQ and CQ combined with SP, 70% and 99%, respectively (p = 0.0006). CONCLUSION: Primaquine exerted no apparent affect on cure of asexual stage parasitaemia, but clearly accelerated clearance of gametocytes. CQ combined with SP was safe and well-tolerated with superior efficacy over CQ for P. falciparum parasitaemia in this study

Determinants of circumcision and willingness to be circumcised by Rwandan men, 2010

<p>Abstract</p> <p>Background</p> <p>Male Circumcision (MC) has been recommended as one of the preventive measures against sexual HIV transmission by the World Health Organization (WHO). Rwanda has adopted MC as recommended but the country is a non-traditionally circumcising society. The objective was to explore knowledge and perception of Rwandan men on Male Circumcision (MC) and to determine the factors associated with the willingness to be circumcised and to circumcise their sons.</p> <p>Methods</p> <p>This cross sectional study was conducted in 29 districts of Rwanda between January and March 2010. Data were collected using a structured questionnaire among men aged 15-59 years. The rate of MC was measured and its perception from respondents, and then the factors associated with the willingness to go for MC were analysed using multiple logistic regressions.</p> <p>Results</p> <p>A total of 1098 men were interviewed. Among respondents 17% (95% CI 14-19%) reported being circumcised. About three-quarter (72%) could define MC, but 37% of adolescent could not. Half of the participants were willing to get circumcised and 79% of men would accept circumcision for their sons. The main motivators for MC were its benefits in HIV/STI prevention (69%) and improving hygiene (49%). Being too old was the main reason (32%) reported by men reluctant to undergo MC and younger men were afraid of pain in particular those less than 19 years old (42%). The willingness to circumcise was significantly associated with younger age, living in the Eastern Province, marital status, and the knowledge of the preventive role of circumcision.</p> <p>Conclusions</p> <p>Adolescents and young adults were more willing to be circumcised. It is critical to ensure the availability of pain free services in order to satisfy the increasing demand for the scale up of MC in Rwanda.</p

Efficacy, Safety, and Tolerability of Three Regimens for Prevention of Malaria: A Randomized, Placebo-Controlled Trial in Ugandan Schoolchildren

BACKGROUND: Intermittent preventive treatment (IPT) is a promising malaria control strategy; however, the optimal regimen remains unclear. We conducted a randomized, single-blinded, placebo-controlled trial to evaluate the efficacy, safety, and tolerability of a single course of sulfadoxine-pyrimethamine (SP), amodiaquine + SP (AQ+SP) or dihydroartemisinin-piperaquine (DP) among schoolchildren to inform IPT. METHODS: Asymptomatic girls aged 8 to 12 years and boys aged 8 to 14 years enrolled in two primary schools in Tororo, Uganda were randomized to receive one of the study regimens or placebo, regardless of presence of parasitemia at enrollment, and followed for 42 days. The primary outcome was risk of parasitemia at 42 days. Survival analysis was used to assess differences between regimens. RESULTS: Of 780 enrolled participants, 769 (98.6%) completed follow-up and were assigned a treatment outcome. The risk of parasitemia at 42 days varied significantly between DP (11.7% [95% confidence interval (CI): 7.9, 17.1]), AQ+SP (44.3% [37.6, 51.5]), and SP (79.7% [95% CI: 73.6, 85.2], p<0.001). The risk of parasitemia in SP-treated children was no different than in those receiving placebo (84.6% [95% CI: 79.1, 89.3], p = 0.22). No serious adverse events occurred, but AQ+SP was associated with increased risk of vomiting compared to placebo (13.0% [95% CI: 9.1, 18.5] vs. 4.7% [95% CI: 2.5, 8.8], respectively, p = 0.003). CONCLUSIONS: DP was the most efficacious and well-tolerated regimen tested, although AQ+SP appears to be a suitable alternative for IPT in schoolchildren. Use of SP for IPT may not be appropriate in areas with high-level SP resistance in Africa. TRIAL REGISTRATION: ClinicalTrials.gov NCT00852371

The association between malnutrition and the incidence of malaria among young HIV-infected and -uninfected Ugandan children: a prospective study

BACKGROUND: In sub-Saharan Africa, malnutrition and malaria remain major causes of morbidity and mortality in young children. There are conflicting data as to whether malnutrition is associated with an increased or decreased risk of malaria. In addition, data are limited on the potential interaction between HIV infection and the association between malnutrition and the risk of malaria. METHODS: A cohort of 100 HIV-unexposed, 203 HIV-exposed (HIV negative children born to HIV-infected mothers) and 48 HIV-infected children aged 6 weeks to 1 year were recruited from an area of high malaria transmission intensity in rural Uganda and followed until the age of 2.5 years. All children were provided with insecticide-treated bed nets at enrolment and daily trimethoprim-sulphamethoxazole prophylaxis (TS) was prescribed for HIV-exposed breastfeeding and HIV-infected children. Monthly routine assessments, including measurement of height and weight, were conducted at the study clinic. Nutritional outcomes including stunting (low height-for-age) and underweight (low weight-for-age), classified as mild (mean z-scores between -1 and -2 during follow-up) and moderate-severe (mean z-scores < -2 during follow-up) were considered. Malaria was diagnosed when a child presented with fever and a positive blood smear. The incidence of malaria was compared using negative binomial regression controlling for potential confounders with measures of association expressed as an incidence rate ratio (IRR). RESULTS: The overall incidence of malaria was 3.64 cases per person year. Mild stunting (IRR = 1.24, 95% CI 1.06-1.46, p = 0.008) and moderate-severe stunting (IRR = 1.24, 95% CI 1.03-1.48, p = 0.02) were associated with a similarly increased incidence of malaria compared to non-stunted children. Being mildly underweight (IRR = 1.09, 95% CI 0.95-1.25, p = 0.24) and moderate-severe underweight (IRR = 1.12, 95% CI 0.86-1.46, p = 0.39) were not associated with a significant difference in the incidence of malaria compared to children who were not underweight. There were no significant interactions between HIV-infected, HIV-exposed children taking TS and the associations between malnutrition and the incidence of malaria. CONCLUSIONS: Stunting, indicative of chronic malnutrition, was associated with an increased incidence of malaria among a cohort of HIV-infected and -uninfected young children living in an area of high malaria transmission intensity. However, caution should be made when making causal inferences given the observational study design and inability to disentangle the temporal relationship between malnutrition and the incidence of malaria. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00527800

Ebola virus disease in West Africa — the first 9 Months of the epidemic and forward projections

BACKGROUND On March 23, 2014, the World Health Organization (WHO) was notified of an outbreak of Ebola virus disease (EVD) in Guinea. On August 8, the WHO declared the epidemic to be a "public health emergency of international concern." METHODS By September 14, 2014, a total of 4507 probable and confirmed cases, including 2296 deaths from EVD (Zaire species) had been reported from five countries in West Africa - Guinea, Liberia, Nigeria, Senegal, and Sierra Leone. We analyzed a detailed subset of data on 3343 confirmed and 667 probable Ebola cases collected in Guinea, Liberia, Nigeria, and Sierra Leone as of September 14. RESULTS The majority of patients are 15 to 44 years of age (49.9% male), and we estimate that the case fatality rate is 70.8% (95% confidence interval [CI], 69 to 73) among persons with known clinical outcome of infection. The course of infection, including signs and symptoms, incubation period (11.4 days), and serial interval (15.3 days), is similar to that reported in previous outbreaks of EVD. On the basis of the initial periods of exponential growth, the estimated basic reproduction numbers (R-0) are 1.71 (95% CI, 1.44 to 2.01) for Guinea, 1.83 (95% CI, 1.72 to 1.94) for Liberia, and 2.02 (95% CI, 1.79 to 2.26) for Sierra Leone. The estimated current reproduction numbers (R) are 1.81 (95% CI, 1.60 to 2.03) for Guinea, 1.51 (95% CI, 1.41 to 1.60) for Liberia, and 1.38 (95% CI, 1.27 to 1.51) for Sierra Leone; the corresponding doubling times are 15.7 days (95% CI, 12.9 to 20.3) for Guinea, 23.6 days (95% CI, 20.2 to 28.2) for Liberia, and 30.2 days (95% CI, 23.6 to 42.3) for Sierra Leone. Assuming no change in the control measures for this epidemic, by November 2, 2014, the cumulative reported numbers of confirmed and probable cases are predicted to be 5740 in Guinea, 9890 in Liberia, and 5000 in Sierra Leone, exceeding 20,000 in total. CONCLUSIONS These data indicate that without drastic improvements in control measures, the numbers of cases of and deaths from EVD are expected to continue increasing from hundreds to thousands per week in the coming months

Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria

Quinine remains an important anti-malarial drug almost 400 years after its effectiveness was first documented. However, its continued use is challenged by its poor tolerability, poor compliance with complex dosing regimens, and the availability of more efficacious anti-malarial drugs. This article reviews the historical role of quinine, considers its current usage and provides insight into its appropriate future use in the treatment of malaria. In light of recent research findings intravenous artesunate should be the first-line drug for severe malaria, with quinine as an alternative. The role of rectal quinine as pre-referral treatment for severe malaria has not been fully explored, but it remains a promising intervention. In pregnancy, quinine continues to play a critical role in the management of malaria, especially in the first trimester, and it will remain a mainstay of treatment until safer alternatives become available. For uncomplicated malaria, artemisinin-based combination therapy (ACT) offers a better option than quinine though the difficulty of maintaining a steady supply of ACT in resource-limited settings renders the rapid withdrawal of quinine for uncomplicated malaria cases risky. The best approach would be to identify solutions to ACT stock-outs, maintain quinine in case of ACT stock-outs, and evaluate strategies for improving quinine treatment outcomes by combining it with antibiotics. In HIV and TB infected populations, concerns about potential interactions between quinine and antiretroviral and anti-tuberculosis drugs exist, and these will need further research and pharmacovigilance