Seguridad de las vacunas frente a rotavirus en niños de la comunidad valenciana, con especial atención a la invaginación intestinal

Résumé

Title Rotavirus vaccine safety in infants from Valencia, Spain, with particular attention to intussusception Doctoral candidate Silvia Pérez-Vilar Introduction Two oral live-attenuated rotavirus vaccines are currently available in the global market: a monovalent human vaccine, Rotarix® (GlaxoSmithKline Biologicals, Rixensart, Belgium), indicated as a two-dose series in infants between the ages of 6-12 and 24 weeks, and a pentavalent bovine-human reassortant vaccine, RotaTeq® (Merck & Co., Inc., West Point, PA, USA), indicated as a three-dose series starting at age 6-12 weeks and ending at age ¿32 weeks. Previously, an observed association between Rotashield®, the first licensed rotavirus vaccine, and intussusception, caused its withdrawal from the US market in 1999, only nine months after licensure. The pre-licensure clinical trials for both Rotarix® and RotaTeq®, designed to exclude an association with intussusception of similar magnitude than that found for Rotashield®, did not find an association. However, after licensure, an increased risk, although of much lower magnitude, was found with both vaccines in Australia, Mexico, Brazil, and the United States. Both vaccines, Rotarix® and RotaTeq®, have been available in Spain since August 2006 and January 2007, respectively. Rotavirus vaccines in Spain are not funded by the National Health System, but are recommended by scientific societies and most paediatricians, and paid for by parents. Due to the incidental finding of circovirus DNA contamination affecting both vaccines, the Spanish Medicines Agency suspended RotaTeq® distribution during June-November 2010, and Rotarix® distribution since March 2010. Intussusception is the most common cause of acute intestinal obstruction in infants. The underlying mechanism remains unknown in most cases; in a few of them it is associated with intestinal malformations or previous intra-abdominal surgery. Incidence varies by age, by sex, being more frequent in males, and by geographic region. Differences observed between regions might be due to racial differences, dietary factors, incidence of infectious agents such as adenovirus or rotavirus, genetics, environmental factors or just reporting differences. The intussusception incidence data from Spain, obtained from hospital-based studies in 1987 and 1990, show high background rates of intussusception, although later publications have shown a notable decreasing trend until 2008. Objectives Our aim was to investigate the post-licensure safety of the rotavirus vaccines in a whole region of Spain, the Valencia Region, with particular attention to intussusception. Methods Several retrospective studies were performed within the framework of this thesis in order to provide a comprehensive post-licensure safety surveillance of the rotavirus vaccines in the Valencia Region: (1) A hospital-based retrospective observational study was carried out to assess the intussusception risk following rotavirus vaccinations using a self-controlled case series (SCCS) design. The SCCS is a case-only design that uses individuals who had the event of interest during the study period; we applied the vaccinated cases-only SCCS approach, which uses only subjects who were exposed to a rotavirus vaccine. Therefore, inference is done within individuals, and time-fixed confounders are controlled implicitly by design. Unvaccinated individuals and individuals for whom vaccination status is unknown were excluded. The observation period (follow-up person-time) for each individual was divided in predefined risk and non-risk periods based on exposure. Therefore, the event of interest falls either into a risk or a non-risk period. The study included assessment of the positive predictive value (PPV) of the intussusception code used in the Spanish hospital discharge database. (2) An ecological study was conducted to assess the intussusception hospitalization rates before and after introduction of the rotavirus vaccines. (3) A descriptive study was performed using the reports of suspected adverse events following rotavirus vaccination as registered in the regional Pharmacovigilance Centre. In addition, the reporting rate for intussusception in the passive surveillance database was compared to the intussusception rate in vaccinated infants obtained using the data from the observational study. The population of interest were resident infants aged less than 10 months. Since rotavirus vaccines are recommended from 6 weeks of age onwards and the observational study was performed using a vaccinated cases only SCCS design (only vaccinated cases were included), the study included only resident infants aged 6-42 weeks, discharged from a public hospital with a diagnosis of intussusception. The period of interest was between 1st of January of 2007 and 31st of December of 2011. Nevertheless, in order to compare the intussusception rates before and after rotavirus vaccines introduction, the analysis included a pre-licensure period. Hospitalized cases irrespective of their rotavirus vaccination status were identified from CMBD, the Spanish hospital discharge database, through the ICD-9-CM code 560.0 in any diagnosis position. A review of hospitalization and primary care medical records of all potential cases among resident infants aged 6-42 weeks was carried out using the standardized Brighton Collaboration case definition for intussusception. First confirmed intussusception episodes (Brighton Level 1-Level 2) were included in the SCCS analyses. In our study, the event date was the date of onset of symptoms. For the ecological study, cases were hospitalization episodes with a discharge diagnosis of intussusception in first or second position. Vaccination status was obtained from SIV, the regional vaccine information system. Lack of information or inconsistencies were confirmed through phone consultation with parents and verbal verification of the information in the child¿s vaccination card. Population data was obtained from the Valencian population-based administrative database, SIP, and passive surveillance data from FEDRA, the database of the Spanish System for the Surveillance of Medications Used in Humans, SEFV-H). Dose-specific incidence rate ratios (IRRs), and their 95% confidence intervals (CI), were assessed to investigate the association between confirmed intussusception cases and rotavirus vaccines within the two predefined risk periods. In our case, the risk periods were defined as days 1-7, and 8-21 post-vaccination, following each dose of any rotavirus vaccine. The comparison (non-risk) period was days 22-42 following each dose. Given the strong confounding effect of age, analyses were adjusted using, as reference, intussusception-hospitalized rates by age in unvaccinated Valencia Region¿s children during the 2001-2011 period. Incidence rate of hospitalizations for intussusception by age in unvaccinated children were estimated using data from CMBD and from the Spanish Statistical Office database (www.ine.es). The PPVs were assessed for the different categories of Brighton Collaboration case classification: (1) Level 1, (2) Level 1-Level 2, and (3) Levels 1-Level 2-Level 3. They were stratified for discharge code position and calendar year. Intussusception hospitalization incidence rates in infants aged <10 months during 2005-2011 were assessed for the pre and post-licensure period using total number of person-years at risk in this population (as registered in SIP). Incidence rates by calendar year with their 95% confidence intervals were also calculated. Observed and expected frequencies by administered dose for non-intussusception suspected adverse events described in the product¿s information were compared using, as denominator, the overall number of doses registered as administered in SIV (as of 20th December, 2012). The reporting sensitivity of the Pharmacovigilance Centre to detect intussusception was calculated by dividing the intussusception-reporting rate to the Pharmacovigilance Centre by the intussusception-observed rate (Level 1 and Level 2 intussusception cases) through the observational study. Since both passive and active surveillance considered the same study period, and the number of rotavirus doses administered were the same, reporting sensitivity was calculated by dividing the reported number of intussusception cases by the observed number of intussusception cases. The risk periods considered were days 1-7, 1-21, 1-30, and 1-42 post-vaccination. All statistical tests were two-sided. Statistical significance was defined as p<0.05. Analyses were performed using Stata/SE 13.1 (StataCorp LP Texas, USA), R 3.0.3 (Foundation for Statistical Computing, Vienna, Austria), SAS 9.2 (SAS Institute, Inc.), and SAS macros developed by Bart Spiessens. The study was approved by the Ethics Research Committee of the Dirección General de Salud Pública/Centro Superior de Investigación en Salud Pública, which provided a waiver to access personal information and contact parents. Results The Valencia Region has an annual birth cohort of around 48,000 infants, among a total population of approximately 5,000,000 inhabitants. Within the population of interest, infants aged 6 to 42 weeks discharged from hospitals of the Valencia Region¿s public health system, 151 potential hospitalized-intussusception cases were identified after having excluded duplicate episodes (children transferred to a reference hospital). Cases occurred in 147 infants, since four infants (3%) had a second episode. Medical records were available for all cases. Among first episodes, 125 cases (85.0%) were classified as Brighton Collaboration intussusception case definition Level 1, 11 (7.5%) as Level 2, two (1.4%) as Level 3, eight (5.4%) as Insufficient Evidence, and one case (0.7%) was discarded. Of 136 confirmed intussusception cases, 35 (26%) occurred in rotavirus-vaccinated children. Among them, 14 (40%), and 21 (60%) had received RV1 and RV5, respectively. Positive predictive value of the intussusception ICD-9-CM code The PPV of the diagnosis code for hospitalized intussusception cases (any discharge diagnosis position) was 93% (95% CI: 87%-96%) for Level 1-Level 2 of diagnosis certainty. No differences by discharge diagnosis position or by calendar year were found. Intussusception risk following rotavirus vaccination Three intussusception cases occurred within days 1-7 following first dose of a rotavirus vaccine (two after RV1 and one after RV5) resulting in a crude IRR point estimate of 9.0 (95% CI: 0.9-86.5), and in an age-adjusted estimate of 4.7 (95% CI:0.3-74.1) within this risk window. Intussusception hospitalization rates before and after introduction of rotavirus vaccines The dynamic cohort of the 2005-2006 period included 116,264 infants younger than 10 months contributing 65,668.8 person-years and 49 events, with an average intussusception incidence rate of 75 per 100,000 person-years (95% CI: 56-99). In the 2007-2011 period, there were 297,144 infants contributing 211,595.9 person-years and 144 events with an average intussusception incidence rate of 68 per 100,000 person-years (95% CI: 58-80). Intussusception hospitalization incidence rates showed a non-significant declining tendency by calendar year. Passive surveillance data: observed and expected frequencies by administered doses The comparison of the observed frequencies (as reported to the Pharmacovigilance Centre) of suspected non-intussusception adverse reactions described in the products¿ information, with the expected frequencies based on clinical trials and post-licensure surveillance, shows that in every case in which this comparison could be made, the observed frequencies were much lower than expected. Passive surveillance versus observational study: Sensitivity reporting for intussusception Two intussusception cases were reported to the Regional Pharmacovigilance Centre as diagnosed during the seven days after any dose of rotavirus vaccine administration. During the same period, four cases were identified within the seven days after any dose of rotavirus vaccine administration by using active surveillance. These four cases were classified according to the standardized Brighton Collaboration intussusception case definition as Level 1 and Level 2 cases. Therefore, reporting sensitivity for intussusception within this risk period was 50%. Reporting sensitivity for 1-21, 1-30 and 1-42 days was 22, 20 y 17%, respectively. Conclusions This comprehensive post-licensure safety evaluation of the rotavirus vaccines in the Valencia Region, a whole region of Spain, includes the first post-licensure observational study of the intussusception risk following rotavirus vaccination in Europe, updated intussusception background rates in Spain, a description of the adverse events reported to the regional Pharmacovigilance centre, and an evaluation of the passive surveillance system to detect the main safety concern of these vaccines, intussusception. We found an elevated intussusception incidence rate point estimate during the first week following first dose, comparable to other studies, although our results were not statistically significant. The study¿s limited power could be the reason for the non-significant findings. Our findings of very few vaccinated cases and decreasing intussusception hospitalization rates despite rotavirus vaccine introduction and a thorough five-year investigation in a country that, according to previous studies, may have a large background rate of intussusception are reassuring. In addition, compared to other passive surveillance systems, the Valencia Region¿s Pharmacovigilance centre has a surveillance system sufficiently sensitive to detect signs of a potential association with intussusception. Therefore, although further analytical studies including larger datasets are required, our results justify the continuing use of rotavirus vaccines in Spain. This study has also shown that a high quality investigation of the safety of childhood vaccinations using Valencia¿s healthcare databases is possible. The high (93%) PPV found for a discharge diagnosis of intussusception has opened the door to the implementation of a larger analytical study without the need to perform medical record reviews. Thus, we plan to continue the observational study for additional years, and also invite participation from other Spanish regions. Moreover, following verification of the PPV of the discharge diagnosis codes in candidate sites, the study could be extended to include other European databases, thus gaining substantial power for the analysis of this rare event, even if vaccination coverage remains low. Such database integration will substantially improve the capacity for timely post-licensure assessments of the safety of any new vaccines introduced in Europe.