Neonatal factors associated with HIV long term non-progressors in a cohort of vertically infected children in Rio de Janeiro, Brazil ("Peixe" Project)

ORIGINAL PAPERS

Neonatal factors associated with HIV long term non-progressors in a cohort of vertically infected children in Rio de Janeiro, Brazil ("Peixe" Project)

Hofer, Cristina B.; Oliveira, Ricardo Hugo; Machado, Elizabeth S.; Pala, Alessandra; Evangelista, Lúcia; Fernandes, Iraina; Abreu, Thalita F.

Universidade Federal do Rio de Janeiro; Rio de Janeiro, RJ, Brazil

^{Address for correspondence}

ABSTRACT

There are only scarce data on HIV progression in vertically infected children in developing countries. The aim of this study is to describe factors from neonatal period associated with long term non-progression (LTNP), in a Brazilian cohort. A cohort study, with data systematically collected from the "Peixe" Cohort (cohort study of children conducted at the main HIV Pediatric Center in Rio de Janeiro, from 1996 to 2005). The study included children who were vertically infected and started follow up at 5 years of age or younger. LTNP, defined as not reaching category C or severe immunosuppression before 5 years of age. Neonatal and demographic factors were studied. Variables with p-value<0.15 were included in a logistic regression model. 213 patients were included, of whom 42% (89/213) were classified as LTNP. Variables independently associated with LTNP were: baseline (at study entry) CD4+ cells (per %) (OR= 1.06, 95%CI=1.01-1.12); age of initiating follow-up, per month (OR= 1.03, 95%CI=1.01-1.06); ZDV use duriing newborn period (OR= 3.31, 95%CI=0.86-12.71); use of antiretroviral (ART) before classification C or severe immunosuppression (OR= 5.89, 95%CI=2.03-17.10). Adjusting for age at the beginning of follow-up, antiretroviral that was unsuccessfully used to prevent maternal-to-child transmission (ZDV use in neonatal period) was associated with better prognosis.

ARTs initiation before category C or severe immunosuppression was also associated with LTNP.

Key-words: HIV, antiretroviral therapy, long term non-progressors, children, Brazil.

It is estimated that 20-40% of HIV-1-infected children present with rapid disease progression and develop AIDS within the first years of life [1-4]. On the other hand, 60-80% of infected children manifest less severe symptoms and many survive through adolescence [3-6]. In developed countries, advanced maternal disease, high maternal viral load, and maternal and infant immune suppression were associated with rapid HIV progression in children [7]. In developing countries, where the majority of perinatal infections occur, there are only scarce data on HIV progression and risk factors. Meanwhile, in some developed countries, all HIV infected children are treated with highly active antiretroviral therapy (HAART) in early infancy. [8]. Brazilian guidelines [9] recommend that HIV infected infants should be treated only if they present any stage B or C symptoms and/or are in immune categories 2 or 3 (CDC) [10]. Although there is some evidence that infants benefit from treatment started in their first year of life, with early HIV replication control and preservation of the immune system [3,4,11], aspects associated with HAART adverse events, adherence and emergence to drug resistant virus must also be considered [5]. Another important issue is the possibility that almost 50% [1-4] of these infants would be long-term nonprogressors (LTNP), and would not benefit from HAART until five years of age or older. It is important to identify early life events that might be associated with long-term nonprogressors, so HAART could be individualized even among infants. The aim of this study is to evaluate neonatal characteristics associated with LTNP in a Brazilian cohort.

Material and Methods

Data were systematically collected from the "Peixe" Project - a cohort study of children conducted at an HIV Pediatric Center in Rio de Janeiro, Brazil, Instituto de Puericultura e Pediatria Martagão Gesteira (IPPMG), from 1996 through 2005. Rio de Janeiro is the second largest city in Brazil and since 1995 573 cases of AIDS in children were notified in this city. Since 1996, all children who were followed up at the IPPMG were enrolled in a prospective cohort study. During their appointments, the health care worker (HCW) who assisted the child was responsible for filling out the cohort forms. The HCW used a pre-validated standardized questionnaire, with demographic, social, epidemiological, clinical, laboratory, and medication data. Prenatal and perinatal data from children who were not followed up in this center since their birth were extracted from maternal prenatal card provided in any health care center in Brazil, where all prenatal and perinatal information are registered and is a very reliable information source. Visits were scheduled at least three times a year, with laboratory evaluations at least twice a year. Children were followed up at least until the age of 13, when they are referred to an adolescent clinic. Children who were vertically infected and started follow up at 5 years of age or younger were included in this study. Exclusion criteria were: lack of birth information or follow-up as an outpatient for less than 1 year.

The main endpoint was LTNP, defined as not reaching category C and/or severe immunosuppression (stage 3) [10] before the age of five years. Early-progressors (EP) were defined as reaching category C and/or severe immunosuppression (stage 3) [10] before the age of five years Neonatal and demographic factors were studied and compared between LTNP and EP.

Statistical Analysis

We evaluated possible risk factors associated with LTNP. Data analysis was performed using Stata version 8.0 statistical software (Stata Corp., College Station, TX). Bivariate analysis was performed using independent t-test (for variables with a normal distribution) or Wilcoxon (Mann-Whiteney) two-sample test (for variables that did not follow the normal distribution). The Chi-square test was used to evaluate associations for categorical variables (or Fisher Exact Test, if 20% or higher of the table cells have an expected value 5 or lower). Variables with a p-value <0.15 were included in the multivariate analysis.

A main-effects logistic regression model was fitted using the stepwise maximum likelihood estimation technique. The level of significance for removal of a variable in backward regression was 0.10, and forward regression was 0.05. Interactions were assessed using the -2 log likelihood ratio test to compare models with and without interactions. The Pearson's Chi-square goodness of fit test, as well as the Hosmer-Lemeshow test, were used to evaluate fitness of the model.

Results

Among 213 patients included, 27% (57/213) were born before 1994. 51% (108/213) were males, 54% (115/213) were considered as non-white (i.e., primarily of African descent), mean birth weight was 3108g, mean age at diagnosis was 21.7 months (ranging 0-59 months), and mean age at which they started follow-up at our Center was 24.7 months (ranging 0-59 months). 42% (89/213) were classified as LTNP. Several factors were associated with LTNP, such as gender, use of intravenous Zidovudine (ZDV) during labor, ZDV use during the newborn period, no history of breastfeeding, age at follow-up initiation, baseline (at study entry) CD4+ cells count and viral load, use of antiretrovirals (ART) before class C diagnosis condition or severe immunosuppression, and use of ART during pregnancy (Table 1).

In the multivariate analysis, factors positively associated with LTNP were: older age at follow-up initiation, higher baseline CD4+ cells (first CD4+ cells count available), ZDV use during the newborn period, and ART use before classification C or severe immunosuppression (Table 2).

Discussion

Factors associated with HIV pathogenesis (higher baseline CD4+ cells count) as well as factors associated with care (ZDV use during the neonatal period, start of ART before patient reaches class C diagnosis condition or severe immunosuppression) were related to LTNP in the 9-year cohort study.

In this cohort, the introduction of ART before patients reached CDC categories C and/or 3 was associated with LTNP. Soh et al. also demonstrated that initiation of protease-inhibitor-based combination therapy before severe immunosuppression was associated with better CD4+ cells recovery [12]. In our study, we also demonstrated that even in patients with higher CD4+ cells, the clinical evidence of immunosuppression (category C) is important to consider when evaluating the exact point to start on HAART.

The use of ZDV during the neonatal period was associated with LTNP, even when adjusting for age at follow-up initiation. The use of ART during pregnancy, labor, and the neonatal period was associated with an important decrease in maternalto-child transmission (MTCT) [13]. These interventions may result in transmission of a resistant HIV strain to the newborn, who then fails prevention strategies, and may also jeopardize the child´s future treatment options [14-16]. In this study we demonstrated that the use of ZDV during the neonatal period was associated with a good long term prognosis. In another study [7], it was associated with a poorer short term prognosis in the bivariate analysis, but when data were adjusted for variables associated with maternal viral load and CD4+ cells count, it was not statistically significant. One hypothesis for the better prognosis found in our study is that exposure to ZDV in the neonatal period may induce viral mutations, leading to a fitness-reduced viral strain [17-19].

Two other studies evaluated the impact of the PACTG076 protocol in children´s prognosis at 18 months [20] or 3 years [21], with divergent results. In the first, a retrospective study, a worse prognosis was found for children who were exposed to ZDV perinatally. In the second, a prospective study, a better prognosis was found for those who started perinatal ZDV. However, this study also found a better prognosis for patients who started earlier ART, and the authors argued that perhaps infants exposed to ZDV perinatally had more contact with the health care system, started earlier ART, and thus had a better prognosis. In this study, probably due to sample size issues, the authors were not able to adjust for it. In our data, we were able to adjust for this possible bias, and we confirmed the findings that neonatal exposure to ZDV is associated with a better long-term prognosis.

The main limitations of our data are that we were not able to retrieve all neonatal information, since some children were adopted or the neonatal files were incomplete or lost, and 27% were born before 1994, before the Protocol PACTG076. On the other hand, this cohort study was derived from a population followed up for a long period, in a systematic matter, in a middle-income developing country where children have access to ARTs. We were able to study separately the three parts of the PACTG076 Protocol; use of ZDV at prenatal, perinatal, and neonatal periods, and newborn use of ZDV was important, even when adjusting for age at ART initiation.

Another important limitation is the fact that not all the children were followed since birth, and the results could be biased by children who died before reach follow up or children who were not diagnosed. However, this study sample size (more than half of cases notified in Rio de Janeiro after 1995) probably is representative from this city HIV infected children. And even if this bias is inserted, this study would demonstrate factors associated with non-progressors in a group of patients followed up in our clinic, and who would probably be the same population frame from other clinics.

In conclusion, we were able to demonstrate that some factors associated with the perinatal/newborn period, such as baseline CD4+ cells count and ZDV use, were associated with a better prognosis, even adjusting for ART use before reaching C and/or 3 category, or the length of follow-up.

Acknowledgements

Conselho Nacional de Pesquisa do Brasil (CNPq)-grant 403373/04-2, for supporting this research. The CNPq had no role in the study design, in the collection, analysis and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication.

Received on 15 March 2009; revised 6 July 2009.

This project was supported by Conselho Nacional de Pesquisa (CNPq)grant 403373/04-2. This study was reviewed and approved by the Instituto de Puericultura e Pediatria Martagão Gesteira Ethical Committee.

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Publication Dates

• Publication in this collection
  04 Mar 2010
• Date of issue
  Aug 2009

History

• Reviewed
  06 July 2009
• Received
  15 Mar 2009