This study represents the first population-based evidence regarding the occurrence and trends of opportunistic illnesses in Brazilian children with AIDS [12
]. The second national cohort study showed a higher proportion of children exposed to HAART, as compared to the first study (65% vs. 35%). However, despite the significant reduction, opportunistic illnesses still were important for AIDS-related morbidity, with more than half of the children with at least one event in the more recent cohort.
The impact of HAART on the reduction of progression to AIDS in children has been described repeatedly [2
], even in developing countries [25
]. However, few population-based studies have evaluated changes in the pattern of occurrence of diseases associated with HIV/AIDS [11
]. Our data show a significant reduction in occurrence of all opportunistic illness in the HAART era: children that were born, or diagnosed with HIV/AIDS or had ART initiation after 1996 consistently and significantly reducing the chances of having opportunistic illness. However we identified a persisting relative importance of some specific events such as invasive bacterial diseases. A study conducted in Italy in a cohort of 1,402 children exposed to HIV through MTCT and representative of the pre-HAART (1985-1995) and HAART (1996-2000 and 2001-2005) periods showed the progressive reduction in the rate of specific clinical events, similar to our study with persisting high rates of serious bacterial infections, particularly pneumonia [11
]. In Brazil, a previous study conducted in Minas Gerais State (Southeast region) in a referral center showed that the effectiveness of HAART was associated with significant reduction in the incidence of opportunistic infections in 371 children observed between 1989 and 2003 [18
]. However, these data were not representative for the AIDS population.
In contrast to these previous studies, we observed that about 1/7 of children still presented P. jirovecii
pneumonia in the HAART era reflecting the late diagnosis and management of HIV infection, despite the significant reduction in the incidence of this event. In our study cryptosporidiosis was significantly reduced (more than five times), as observed in other studies [11
]. For other diseases (excluding cryptococcosis), despite the indication of reduction in the proportion of cases in the second period, there was not a significant difference between the periods.
Children with AIDS diagnosed between 1996-2002 had a three times lower odds of having opportunistic infections, as compared to those born before the release of any ARV. Thus, they had the chance to be treated with ARV, even in advanced stages of HIV infection [6
Operational issues related to health services examined in this study, as the realization of prenatal care and adoption of breastfeeding were not significantly associated with the occurrence of opportunistic events, the first guidelines for management of HIV infection and opportunistic diseases were published in 1994, and the first therapeutic consensus was established in 1996. Expanded further actions for the prevention of MTCT have occurred since 1999 [6
]. Despite these advances in national policy for control of HIV [13
], there are indications of operational failures in these procedures [30
]. Additionally, regional differences are important factors that contribute in Brazil to sustain a non-favorable outcome [16
]. Our study points to a statistically significant association between non-performance of any measure aimed at the prevention of MTCT (prenatal or childbirth or child) and the occurrence of these clinical events. Approximately one seventh of the children had undergone some of the interventions to prevent MTCT, but still acquired HIV and developed AIDS. Probably, ongoing care and routine monitoring of children exposed to HIV would have prevented opportunistic illnesses in these cases. The vast majority of children in this study was born after 1995 (and about half of them after 1997), after wide implementation of MTCT control measures, evidencing a missed opportunity to prevent HIV transmission and to start HAART early.
We identified a positive association between the occurrences of opportunistic illnesses in all regions of the country compared with the North region, mainly in the Southeast where the epidemic is consolidated since the very beginning [30
]. It is noteworthy that the North region had the lowest proportion of AIDS cases in the two periods (2% vs. 9%). After the period analyzed in these two cohorts, the North had a progressive increasing of incidence and mortality rates related to AIDS, which may have led to changes in the relative occurrence of these events when comparing regions [13
Children aged < 1 year of age had a higher frequency of opportunistic illness compared with children aged 1-5 and 6-12 years. This population of children is known to progress more rapidly to AIDS, with strong evidence of efficacy of early treatment [4
], which indicates the need for earlier interventions for the treatment of HIV infection. Based on this evidence, since 2009 Brazil has adopted measures on their therapeutic guidelines recommending the treatment of all HIV infected children < 1 year of age regardless of clinical symptoms, immunological classification or HIV viral load [35
This study is based on the two unique national cohorts of children with AIDS for survival analysis with a representative number of children with AIDS in the country and its regions. Considering the sheer magnitude of the analyzed period (1983-2007), measures adopted for data collection were standardized, with a systematic review of all data collected, and minimizing the effects related to changes in criteria for AIDS cases definition, management/diagnosis of opportunistic infections and ART.
The present study has limitations beyond those already identified and described extensively in our previous publications on the topic [14
]. Children in both cohorts had differing criteria for AIDS case definition, with greater sensitivity in the last one [6
]. This may underestimate the occurrence of opportunistic diseases in this cohort. The presumptive diagnosis in health services may be related to difficulties of clinical diagnosis in some cases, the nature of each specific disease, technical conditions, such as provision of technical conditions for complementary diagnosis and experience of medical professionals with HIV/AIDS in children. Moreover, issues such as underreporting of clinical events and drop-out of some children during the periods specified in the two survival studies may have biased our results.
Considering the study period (1983-2007) and the advance of the Brazilian policy for the control and management of HIV infection/AIDS even after the introduction of HAART, the period after 2002 may have possibly a different pattern of occurrence of opportunistic conditions, indicating the need for further studies.