a Department of Paediatrics, University of Florence, Florence, Italy.
b Department of Paediatrics, University of Turin, Turin, Italy.
c Epidemiology Unit, Centre for the Study and Prevention of Cancer, Careggi Hospital, Florence, Italy.
Reprint requests to: Prof. Maurizio de Martino, Coordinator of the Italian Register for HIV Infection in Children, Department of Paediatrics, University of Florence, Via Luca Giordano 13, I-50132 Florence, Italy. E-mail: mdm{at}ao-meyer.toscana.it
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Abstract |
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Methods Prospective study on 366 perinatally infected children followed-up from birth and checked at least every 2 months. Survival, smoothed hazard, adjusted hazard ratio of death, and transition probabilities in clinical and immunological categories were outcome measures.
Results Survival was 49% (95% CI : 4058%) at 8 years. The risk of death was high before the age of 2, relatively low between ages 2 and 7, and contained thereafter. Children did not advance through the categories sequentially. Survival at 8 years was 61.7% (95% CI : 49.873.6%) in those children who had passed through clinical category A; the hazard ratio of death was 2.5 (95% CI : 1.73.8) for 175 (47.9%) children who skipped this category. Transition probability in clinical category B was 39.9% (95% CI : 32.345.6%) after one year, but 59.1% (95% CI : 51.466.8%) after 5 years. Before 2 years of age, the probability of entry into category C (40%; 95% CI : 3545%) was higher than that of entry into immunological category 3 (28%; 95% CI : 2234%).
Conclusions The classification system stands comparison with the clinical reality, but the CD4-positive cell thresholds in infancy should be adjusted and category B indicator diseases better distributed to improve their predictive value.
Keywords CD4-positive lymphocytes, CDC paediatric classification system, disease progression, perinatal HIV-1 infection, survival
Accepted 27 October 1999
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Introduction |
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Patients and Methods |
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Data are collected through registration and follow-up forms which contain questions on child's demographic data, age at first observation, maternal data (including clinical condition at the time of delivery), perinatal data (including gestational age, birthweight, and type of infant feeding), HIV-1 antibodies, virus markers (proviral DNA, virus culture, free and complexed p24 antigenaemia), CDC classification, CD4-positive cell numbers (measured by standardized fluorescent-activated cell sorting technique),4 laboratory tests, HIV-1 related signs and age at the appearance of single signs, the age at the entrance to the clinical and immunological categories of the CDC paediatric classification system or at death, Pneumocystis carinii pneumonia (PCP) chemoprophylaxis, drug used for PCP chemoprophylaxis, date at the beginning and end of chemoprophylaxis with each drug, antiretroviral therapy (ART) and drug(s) used, date at the beginning and end of therapy with each antiretroviral drug, date at last check-up or at death (with causes). Forms are completed every six months by the appointed paediatrician at each centre.7 Quality checks are carried out in duplicate on all forms by the two co-ordinating centres before any data are entered into specific software. Further checks are subsequently carried out on all data included in the database. Paediatricians from participating centres meet at least once a year to audit proceedings and standardize procedures. According to these, all infected children (independently of their clinical condition) are examined both clinically and immunologically at least every 2 months, and the exact date of any clinical and of any confirmed immunological changes are reported in the follow-up form.
Case definition
The whole cohort of 366 children definitely infected and enrolled before 30 June 1997, were studied. Infection was diagnosed through detection (on at least two occasions) of virus markers, or the persistence of HIV-1 antibodies after 18 months of life, or the onset of AIDS-defining signs.3 The CDC classification system defined the clinical and immunological condition.3 This system provides mutually exclusive states based on the intersection of four clinical and three immunological categories. Clinical categories classify children with no (category N), mild (category A), moderate (category B), or severe (category C) AIDS-defining signs. Immunological categories are based on thresholds of CD4-positive cell numbers adjusted by age and distinguish no (category 1), moderate (category 2) and severe (category 3) immunosuppression. The criteria for HIV-1 related disease used in defining the CDC clinical categories have been previously reported.68
The status of each subject at this analysis was the one attributed at the date of last clinical check or death. Only HIV-1 related deaths were considered when survival was estimated;68 subjects whose death was not directly attributable to HIV-1 infection were censored at last check. No standardized criteria exist to define long-term non-progressors (LTNP). We defined as LTNP those children surviving longer than the median survival and classified as N1 or A1 (category N and A signs do not predict negatively).68 The CDC classification for HIV-1 infection in adults was used in defining mothers' clinical condition at the time of delivery.9
Statistical analyses
Data were processed by SPSSX (SPSS Inc., Chicago, IL) and EGRET (SERC Software Division, Washington, DC) statistical packages. Ages were reported as median and range. The transition probability (i.e. the cumulative probability of moving from one category to a worse one or death within one and 5 years) was calculated by the Kaplan-Meier product-limit method; the 95% CI were estimated on the basis of Greenwood estimate of variance using a transformation to avoid impossible values.10,11 Differences in curves were tested by the Log-rank test. To describe the pattern of hazard of dying over time, smoothed hazard curves (according to the Kernel function) were plotted with bandwidths of 12 months.12 Cox proportional hazard methods were used to evaluate factors independently associ-ated with survival and the clinical course. Covariates entered into the model were gender, year of birth (as a continous variable), gestational age (<36 weeks versus >36 weeks), birthweight (<2400 g versus >2400 g), mother's clinical condition at the time of delivery (asymptomatic category A [276] versus symptomatic category B [51] and C [4] women), type of infant feeding (ever breastfed versus exclusively formula-fed) and treatments (no treatment, PCP chemoprophylaxis, ART, PCP chemoprophylaxis and ART). First, all covariates were adjusted for each other. Then, the variables were selected according to backward elimination procedure.13 In assessing the transition probability from a specific category, only treatments received after entry into that category and before passage to a worse one or death were considered (to avoid the bias of treatments given as a consequence of a worsening in the clinical or immunological course). To define history in infancy, children aged <18 months at the time of analysis (33) were also included. Since some centres in our Register did not have facilities to routinely carry out PCR or viral culture, it was possible that some severely affected infants <18 months were identified as HIV-1 infected and entered the study, whereas other asymptomatic age-matched infants were not identified as HIV-1 infected and did not enter the study. Because this could bias the results, survival was compared in children aged < or >18 months and probability of entering category C and survival were calculated also excluding the former children. Two (i.e. the end of the first peak of mortality in the bimodal course of perinatal infection)68 and 8 years of age (end of our follow-up) were chosen as ages to compare survival and timing of entry into clinical and immunological categories.
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Results |
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Discussion |
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The second downfall is a poor predictive significance for clinical category B, either a long-lasting stage of moderate disease (59.1% transition probability after a 5-year period in this category) or the threshold to AIDS (39.9% probability of progression to AIDS after one-year period). Category B indicator diseases are widely different in prognostic importance68 and distributing indicator diseases, according to criteria of predictivity, could make the classification system more suitable to clinical reality. A high-risk subcategory B could include anaemia, candidiasis, cardiomyopathy, diarrhoea, hepatitis, and persistent fever. We have previously shown that these category B signs are those significantly associated with a shorter survival.68
Different from the previously proposed Markov chain modelling,15 children do not advance through the categories in sequence and category A singles out a more favourable state than even category N, from which half of the children move directly into category B or AIDS. High transition probability in category N is the result of a short symptom-free period, due to the infants' immunological immaturity and permissiveness towards HIV-1.8 The category A signs resemble the adults' diffuse infiltrative lymphocytosis syndrome rather than the acute clinical syndrome, which correlates with short survival.7 Category C is highly discriminatory because it is the almost unique category at risk of death; 44.9% of category C children die within one year after entry in this category. Category 3 is less discriminatory (28.6% of category 3 children die within one year after entry in this category and only 63.4% of children die in this category before the age of 3 years) probably due to circulating CD4-positive cell numbers which are unrepresentative of the total body pool.7 The short survival of infants who rapidly enter category 3 confirms that dynamic data of CD4-positive cell loss, rather than static data, have a predictive meaning.4,7
Long-term non-progressors are a negligible portion of infected children, due also to the fact that subjects cannot be reclassified into a less severe category even if their clinical or immunological status improves.1,3 Nevertheless, children have a relatively slow progression besides some infants who rapidly develop AIDS and die probably because of virus transmission in utero, early altered immunity, and a high viral load.4,7,8,16 The risk of death slowed somewhat after 7 years of life, even though we must be careful due to the number of events and sample size at older ages. Due to these limitations a longer follow-up of our cohort is needed to confirm this pattern.
Differences in the outcome may be associated with year of birth,17 mothers' clinical condition at the time of delivery,18 birthweight,8 and type of infant feeding.19 In addition there is recent evidence that children infected in spite of maternal ZDV treatment in pregnancy have a particularly severe outcome.20 We did not consider maternal ZDV treatment as a covariate because the whole data set of children (born since 1984) was taken into account in the present study whereas children born to ZDV-treated mothers were born after 1992. Since the standard of care has been radically changed over time, any comparison between these two groups would be misleading.
The lack of significance of such factors in our analysis probably does not depend on their lack of importance. Rather, the strong association between the outcome and treatments overpowered any other statistical significance (only year of birth, which correlates with treatments,17 neared significance). The effectiveness of PCP chemoprophylaxis and the benefits of ZDV and ddI treatments in children have been demonstrated.21,22 The lower progression in immunological categories when ART is given is revealing, since it may be that ART slows down CD4-positive cell loss.22 However, the effects of treatment on survival, as observed in the present study, need to be considered with caution: some severely affected children may not have received treatment because of course rapidity (overestimating the effect) and some mildly affected children may not have received treatment because their clinical condition did not require it (underestimating the effect). Treatments could be also an indicator of factors (e.g. family compliance, socioeconomic status, attention and care devoted to the child) which may effect the outcome.23 It is unlikely that the small number of children lost to follow-up biased results since slight differences in clinical categories, as compared to the remaining study population, were representative of their younger age. Findings may be relevant in clinical management, family counselling, health policies, and trial design. The classification system supports the long-term clinical course satisfactorily, but may not predict the prognosis in all age groups and categories. The results of the present study are important also in that they incorporate treatments in multivariate analysis, along with other more traditionally recognized variables related to disease progression. The fact that the treatment variables overcome these other variables adds to the literature because previous studies have not had enough treated subjects to be able to establish the importance of treatment in relation to disease progression. The adoption of HAART at a progressively earlier stage in most children14,24 will probably bring about further radical changes in the long-term course of the infection. The present study aimed to give an outlook on the long-term course of perinatal HIV-1 infection and provide Italian data on the suitability of the 1994 CDC classification system, comparing the results with those of other large multicentre studies carried out in the pre-HAART era in France1 and USA.2
Any future analysis of outcome in perinatally HIV-1 infected children will be compared with the clinical course as outlined in the present study in children of untreated mothers and receiving pre-HAART regimens.
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Appendix |
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Acknowledgments |
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References |
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