In silico calculated affinity of FVIII-derived peptides for HLA class II alleles predicts inhibitor development in haemophilia A patients with missense mutations in the F8 gene.

Forty per cent of haemophilia A (HA) patients have missense mutations in the F8 gene. Yet, all patients with identical mutations are not at the same risk of developing factor VIII (FVIII) inhibitors. In severe HA patients, human leucocyte antigen (HLA) haplotype was identified as a risk factor for onset of FVIII inhibitors. We hypothesized that missense mutations in endogenous FVIII alter the affinity of the mutated peptides for HLA class II, thus skewing FVIII-specific T-cell tolerance and increasing the risk that the corresponding wild-type FVIII-derived peptides induce an anti-FVIII immune response during replacement therapy. Here, we investigated whether affinity for HLA class II of wild-type FVIII-derived peptides that correspond to missense mutations described in the Haemophilia A Mutation, Structure, Test and Resource database is associated with inhibitor development. We predicted the mean affinity for 10 major HLA class II alleles of wild-type FVIII-derived peptides that corresponded to 1456 reported cases of missense mutations. Linear regression analysis confirmed a significant association between the predicted mean peptide affinity and the mutation inhibitory status (P = 0.006). Significance was lost after adjustment on mutation position on FVIII domains. Although analysis of the A1-A2-A3-C1 domains yielded a positive correlation between predicted HLA-binding affinity and inhibitory status (OR = 0.29 [95% CI: 0.14-0.60] for the high affinity tertile, P = 0.002), the C2 domain-restricted analysis indicated an inverse correlation (OR = 3.56 [1.10-11.52], P = 0.03). Our data validate the importance of the affinity of FVIII peptides for HLA alleles to the immunogenicity of therapeutic FVIII in patients with missense mutations.

Implementation of a hepatitis A prevention policy in haemophiliacs: results from the French cohort.

In the early nineties, the occurrence of hepatitis A outbreaks in some patients with haemophilia in some countries led French health authorities to recommend hepatitis A virus (HAV) vaccination in HAV-seronegative haemophiliacs. The French 'Suivi thérapeutique National des Hémophiles' cohort permitted to assess the implementation of this recommendation by the analysis of the vaccinal process, i.e. HAV seropositivity assessment and vaccination of HAV-seronegative patients, in a survival approach. In a subgroup of 812 patients diagnosed earlier than 1990 (prevalent cohort), the implementation of vaccinal process increased quickly from 0% in 1993 to 41.8% in 1994 and to 71.2% in 1996, suggesting a 'notification effect'. The vaccinal process was associated to three cofactors in a Cox model analysis (age, severity of haemophilia, centre of treatment). No infection was observed during the survey in this group. In another subgroup of 201 boys born since 1993 (incident cohort), 27.5% and 15.4% patients remained exposed to the risk at 3 and 5 years from diagnosis respectively, again with a 'centre effect', which might be linked to various factors such as regain in confidence for products or economic reasons. Only five infectious seroconversions were assessed over the 7-year survey, which represents 14.5 cases per 1000 person-year incidence without any relationship with products. Our data combined with the contemporary hepatitis A epidemiology and the current safety of anti-haemophilic concentrates, should lead to a new assessment of the risk of hepatitis A in haemophiliacs. We suggest that among patients with bleeding disorder, as well as in other populations, HAV prevention policy might be stressed on those who already suffer from chronic liver disease and/or travel in endemic countries.

Introduction of an obstetric health information system: results of a pilot study in North Cameroon.

BACKGROUND: International safe motherhood programs have placed increasing emphasis on assessing progress in reducing maternal mortality in developing countries. We assess the feasibility and relevance of an obstetric health information system introduced in Maroua urban district in North Cameroon. METHODS: During the study period, an obstetric observation register was introduced for obstetric data collection, complemented by anthropological case studies on maternal deaths. RESULTS: At the end of the study period, implementation and data collection processes were correctly done, and the overall rate of completion of obstetric registers was 95% (ranging from 82.5% to 98.5% between maternity units). Eight hundred and twenty-six deliveries (n=826) were recorded and evenly distributed over the nine weeks of the study period. Eight women (1%) were transferred from non-surgical to surgical health facilities. Thirteen C-sections (n=13; 1.6%; CI: 0.8-2.7%) mainly in the provincial hospital of Maroua (11/13), and four maternal deaths were recorded, giving a maternal mortality rate of 4/826 (484 for 100,000; CI: 132-1240 for 100,000 deliveries). Nevertheless, anthropological enquiry recorded five maternal deaths during the same study period. Analysis of the geographical origin of these women showed that four of the five came from very remote areas. Rapid analysis and dissemination of results have initiated changes in obstetric practices (introduction of the partograph, modifications in the attitudes of health personnel), and also to the creation of a network between maternity units (those with and without surgical facilities) and provincial health headquarters. CONCLUSION: The introduction and use of a basic obstetric health information system combined with anthropological survey can provide a relatively accurate assessment of the maternal health situation. Such knowledge would be an excellent basis for implementing obstetric networking and relevant tools for active management of the obstetric pyramid at a regional level in developing countries.

Intracranial haemorrhages in French haemophilia patients (1991-2001): clinical presentation, management and prognosis factors for death.

Intracranial haemorrhage (ICH) is known to be a severe although uncommon complication of haemophilia. A national survey has been conducted in France in order to collect information about ICHs which occurred in haemophiliacs between 1991 and 2001 and to propose recommendations for the diagnostic and treatment of ICH. Within this period, 123 episodes of ICH were recorded from 106 patients. Two-thirds of ICH concerned patients with severe haemophilia. Half of the cases occurred in patients under 15 years of age, 67.2% of which were post-traumatic. Ten cases occurred in neonates with three fatal outcomes. Overall mortality was high (21.9%) suggesting that availability of clotting factor concentrates has not improved the prognosis of this event. Morbidity was also high with 60% of long-term sequelae. The following parameters have been identified as prognostic factors for death: thrombocytopenia, HCV infection, intraventricular or intraparenchymatous haemorrhage. A delay in diagnosis was mentioned in 43.3% of cases, often related to the lack of recognition of the initial symptoms, which may be very common (apathy, tearfulness in young children and headache in elder patients). Delayed replacement therapy was recorded in 37.2% of cases. Emergency units initially dealt with half of these patients. Information concerning recognition and management of these episodes, not only in severe haemophilia, but also in moderate and mild forms, should be regularly supplied to paediatricians in maternity and physicians from emergency units, as well as to patients and their relatives.

The French haemophilia cohort: rationale and organization of a long-term national pharmacosurveillance system.

Medicinal products of biological origin still carry a specific iatrogenic risk, mainly because of their starting material, mode of preparation and variability. Careful postmarketing surveillance systems are therefore necessary. To assess the long-term safety of haemophilia treatment with plasma-derived and recombinant clotting factor products, a cohort study was set up in France in 1994. Participants were patients with haemophilia A and B, with or without previous clotting factor therapy. Clinical events, treatments, biological data and adverse events were recorded on standard forms. Blood samples were separated into serum, plasma and peripheral blood mononuclear cells, frozen, and banked in a central laboratory. The same data and samples were collected at yearly follow-up visits. As of December 1999, 1234 haemophiliacs were enrolled in 39 haemophilia centres. At enrollment, 50.2% of patients were under 15 years of age, and the cumulative number of days of exposure to the product was below 50 in 35.1% of cases. The median duration of follow-up was 26.9 months, with a total of 2729 patient-years (135,947 days of exposure and 211 million units of factor VIII or IX). To date, only 17 patients were lost to follow-up. The initial results show good compliance with this health-watch policy among patients and clinicians specializing in haemophilia. The regular follow-up data and centralized sample bank will serve to investigate rapidly any suspected outbreaks as soon as reliable biological tests become available in the future.

Prevalence and determinants of current contraceptive method use in a palm oil company in Cameroon.

The principal reasons given by African women for not using contraception include their lack of economic power and control over their choice of partner. An epidemiologic descriptive survey of a cross-section of the female personnel of a Cameroonian palm oil company (SOCAPALM) was carried out in August 1995, to evaluate the various determinants and level of use of various family planning methods in a well defined population of women in employment. An exhaustive list of all the households in the five villages of SOCAPALM was compiled and all women between 15 and 49 years of age who had lived on the palm oil plantation for at least a year were interviewed. The adjusted odds ratios showed that use of modern contraceptive methods was significantly associated with the woman having received secondary education, having more than three children, being the head of the household and, in cases where there was a man regularly present in the household, his approval of family planning. Recently receiving information (during the last month) about family planning was not identified by multivariate analysis as a significant factor affecting the decision to use modern or traditional contraception. The same factors were found to be associated with the use of traditional methods of contraception, but having had an illegal abortion was also associated with the use of such methods. Thus, the level of knowledge about family planning and the prevalence of contraceptive use was significantly higher for women living in industrial environments (such as SOCAPALM), than in the overall population of women in Cameroon. The economic power of the woman, the presence of a strong social reproductive health network, and the positive attitude of men and community leaders were the most important factors affecting the family planning decision of the women.

PIP: The prevalence and determinants of contraceptive usage were investigated in a cross-sectional study of female workers at a palm oil company in Kienke, Cameroon. All 385 women 15-49 years of age (mean age, 29.8 years) who had lived on the palm oil plantation for at least a year and were at risk of pregnancy were interviewed. 28% of respondents reported ever-use of modern contraception and 21% had used traditional methods; use rates at the time of interview were 10% and 16%, respectively. Multivariate analysis indicated use of modern contraceptive methods was significantly associated with a secondary education or higher, having more than three children, being the head of the household, and (if a man was present in the household) partner approval of family planning. These same factors, with the addition of a history of illegal abortion, were significant determinants of use of traditional methods. Receipt of family planning information in the previous month was not a significant determinant of use of either modern or traditional contraception. The higher prevalence of contraceptive use among women living in this industrial environment relative to women in other parts of Cameroon or in west and central Africa suggests the salience of economic power to women's contraceptive use patterns.

[Obstetric complications of the first trimester in Western Africa]. / Complications obstétricales du premier trimestre en Afrique de l'Ouest.

The obstetrical complications affecting women in Benin, Senegal and Ivory Coast during the first trimester of pregnancy were studied. Information about the 345 women included in the study was collected from registers maintained by the eight participating maternity units. The most frequent complications observed were spontaneous abortions (50% of admissions), complications of induced abortions (34%), and ectopic pregnancy (8%). Overall, the patients appear to have gained rapid access to care: two thirds of the women underwent interventions on the day of admission. Nevertheless, there were three maternal deaths, two of which followed induced abortion complications.

[Risk of the appearance of inhibitors linked to the administration of factors VIII and IX. Review of the literature]. / Risque d'apparition d'inhibiteurs liés à l'administration de facteurs VIII et IX. Revue de littérature.

Factors VIII and IX administration exposes haemophiliac patients to the risk of inhibitor development which reduces treatment efficacy. Methods and results of 17 studies (transversal and longitudinal) and of one clinical trial dealing with haemophilia A and of 3 studies dealing with haemophilia B were reviewed. Besides differences in study design, lack of method standardisation complicates comparison between studies. In patients with haemophilia A, prevalence of inhibitors ranges from 4 to 18% (5 studies), and incidence between 3 and 39/1,000 person-years (7 studies). Cumulative age incidence is above or equal to 20% after 6 years of age (4 studies). Cumulative incidence by exposure days is estimated at 22% at 100 exposure days in a retrospective cohort observed between 1975 and 1992, and above or equal to 36% at 25 exposure days in two prospective cohorts of patients receiving recombinant factor VIII products. The new European regulation dealing with stable blood products will make the evaluation of new products by clinical trials mandatory. With The National therapeutic Follow up of Haemophiliacs which begun in October 1994, following a decision by the French Minister of Health, the adverse effects in patients receiving factor VIII and IX which have been approved for sales will be evaluated.

Randomized study of two doses of didanosine in children infected with human immunodeficiency virus.

2'3'-Dideoxyinosine (didanosine) is a nucleoside analog active in vitro against human immunodeficiency virus. Few data are available regarding its use for the treatment of children. In a single-center, randomized, open-label trial, we compared two dosages of didanosine (120 vs 270 mg/m2 per day) for at least 6 months in 34 children infected with human immunodeficiency virus who had become resistant to or were intolerant of zidovudine. Serum levels of didanosine 1 hour after administration were significantly different in the two groups and remained stable with time. There was a significant reduction in human immunodeficiency virus-p24 antigenemia and quantitative cellular viremia with time but no difference between the two groups. The intensity of the biologic response, however, was significantly higher in the patients who had more than 50 CD4+ cells 10(6)/L at inclusion. No pancreatic or neurologic toxic effects were observed. In five children, liver function abnormalities developed that are unusual in this setting, and the death of one child from unexplained hepatocellular failure suggests that didanosine may be hepatotoxic. Three of these five children had preexisting liver disease. Although no definite conclusion can be made as to the optimal dose, there were no major differences between the two administration schedules in terms of biologic effects and tolerability.