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Cancer Rates After Year 2000 Significantly Decrease in Children With Perinatal HIV Infection: A Study by the Italian Register for HIV Infection in Children

Elena Chiappini, Luisa Galli, Pier-Angelo Tovo, Clara Gabiano, Catiuscia Lisi, Carlo Giaquinto, Osvalda Rampon, Guido Castelli Gattinara, Giulio De Marco, Patrizia Osimani, Mariano Manzionna, Angela Miniaci, Carlo Pintor, Raffaella Rosso, Susanna Esposito, Alessandra Viganò, Icilio Dodi, Anna Maccabruni, Carlo Fundarò, Maurizio de Martino

From the Departments of Pediatrics and Statistics, University of Florence, Florence; Department of Pediatrics, University of Turin, Turin; Department of Pediatrics, University of Padua, Padua; Bambino Gesù Children's Hospital; A. Gemelli Hospital, Rome; Department of Pediatrics, Federico II University, Naples; Salesi Children's Hospital, Ancona; Biomedic Department, University of Bari, Bari; Pediatric Clinic III, University of Bologna, Bologna; Pediatric Clinic, University of Cagliari, Cagliari; Infectious Disease Unit, University of Genoa and S. Martino University Hospital, Genoa; Institute of Pediatrics, University of Milan, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena; Pediatric Clinic, Sacco Hospital, University of Milan, Milan; Pediatric Infectious Disease Unit, Parma; and Infectious Disease Department, University of Pavia, Pavia, Italy

Address reprint requests to Maurizio de Martino, MD, Department of Pediatrics, University of Florence, Via Luca Giordano, 13, I-50132 Florence, Italy; e-mail: maurizio.demartino{at}unifi.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose To evaluate the impact of highly active antiretroviral therapy (HAART) on cancer incidence in HIV-infected children throughout a 20-year period.

Patients and Methods An observational population study was conducted on 1,190 perinatally HIV-infected children enrolled onto the Italian Register for HIV Infection in Children from 1985 to 2004 and never lost to follow-up (total observation time, 10,037.66 years). Cancer rates were calculated in the pre-HAART (1985 to 1995), early HAART (1996 to 1999), and late HAART (2000 to 2004) periods and compared using Poisson regression adjusted for age. The proportion of HAART-treated children increased from 4.1% in 1996 to 60.4% in 1999 and to 81.5% in 2004. In the same time frame, the proportion of children receiving HAART for at least 2 years increased from 3.1% to 77.0%.

Results Overall, 35 cancers occurred. Cancer rates were 4.49 (95% CI, 2.37 to 6.64), 4.09 (95% CI, 1.68 to 6.50), and 0.76 (95% CI, 0.00 to 1.80) per 1,000 children per year in 1985 to 1995, 1996 to 1999, and 2000 to 2004, respectively. Notably, there was no significant difference comparing the periods from 1985 to 1995 and 1996 to 1999 (P = .081). By contrast, cancer rates were significantly lower in the period from 2000 to 2004 than in 1996 to 1999 (P < .0001). Results were confirmed by separately analyzing data from children observed from birth (P = .418 for 1985 to 1995 v 1996 to 1999; P = .001 for 1996 to 1999 v 2000 to 2004).

Conclusion Dramatically reduced cancer rates were observed only in the late HAART period in parallel to the increasing proportion of children receiving HAART therapy.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
The beneficial impact of highly active antiretroviral therapy (HAART) on mortality in children with perinatal HIV infection is well-documented,¹ but whether increased duration of life has led to a changed risk of HIV-associated cancer has not been elucidated yet.² In adults, substantial reductions in the incidences of some HIV-related malignancies have been reported,³ but data in children are limited.^4-6 A previous study on patients enrolled onto the Italian Register for HIV Infection in Children until 1999⁷ did not show a declining rate of cancer in the first HAART era. This finding could be affected by the short follow-up period. Therefore, we conducted a similar analysis extending the observation to more recent years.

	PATIENTS AND METHODS

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Study Design
An observational population study was conducted on perinatally HIV-infected children enrolled onto the Italian Register for HIV Infection in Children^1,8 from 1985 to 2004 and never lost to follow-up. The rates of malignancies in the pre-HAART and early and late HAART periods were assessed.

Data Collection
Data were collected by the Italian Register for HIV Infection in Children, which is a nationwide multicenter study of children vertically exposed to HIV instituted in 1985 by the Italian Association of Pediatrics.^1,8 The data source is a network of 106 pediatric clinics distributed throughout Italy that has been previously demonstrated to be highly representative of the whole population of Italian HIV-1–infected children.¹ Information concerning data collection has been described in detail elsewhere.^1,8 Briefly, the standard registration form consists of demographic and perinatal data. Both the registration and the follow-up forms contain data regarding infectious status; clinical events, including malignancies; laboratory tests; and treatment. The forms are filled out by an appointed pediatrician at each center. Data collection started on June 1, 1985. In the present study, data collected up to December 31, 2004, were analyzed. To avoid potential selection bias,⁵ data from children who were lost to follow-up were analyzed separately.

Malignancies
All cancers that developed during the observation time in the study children were included in the analyses. Both AIDS-defining cancers (brain lymphomas, small noncleaved-cell non-Hodgkin's lymphoma [NHL], immunoblastic or large-cell lymphoma of B cell or unknown immunologic phenotype, and Kaposi's sarcoma)² and other cancers (ie, leiomyosarcoma, cervical carcinoma, hepatoblastoma, or acute lymphoblastic leukemia) were considered. One patient with osteochondroma was excluded. To assign cancer diagnoses, specialized pathology review was performed at each local university center.

Laboratory Investigations
CD4⁺ T-lymphocyte counts were measured by standardized fluorescent-activated cell sorting technique. According to the US guidelines for the use of antiretroviral agents in pediatric HIV infection,⁹ CD4⁺ T-lymphocyte percentages, rather than their absolute counts, were taken into account because these percentages reflect the immune status of HIV-infected children more accurately.

Treatment
The specific therapy offered was based on Italian and US guidelines.^2,8 Only therapeutic courses administered for at least 30 days were considered in the study.¹ HAART was defined as a combined antiretroviral therapy including at least two nucleoside reverse transcriptase inhibitors and one protease inhibitor or two nucleoside reverse transcriptase inhibitors and one non-nucleoside reverse transcriptase inhibitor. In our study population, the proportion of HAART-treated children increased from 4.1% in 1996 to 60.4% in 1999 and to 81.5% in 2004. Moreover, the proportion of children taking HAART for at least 2 years increased from 3.1% in 1996 to 1999 to 77.0% in 2000 to 2004.

Calendar Periods
The breakpoint between the pre- and post-HAART periods in 1996 is well-documented.¹ A previous study on children enrolled onto the Italian Register until 1999 did not demonstrate a declining rate of cancer in the first years of the HAART era.⁷ Thus, it was decided to analyze separately the pre-HAART (1985 to 1995), early HAART (1996 to 1999), and late HAART (2000 to 2004) periods.

Statistical Analysis
Age was expressed as median and range. CD4⁺ T-lymphocyte percentage was expressed as mean and standard deviation. Cancers were assigned to the time period during which the diagnosis was made, and the number of events per 1,000 child-years of observation time in the corresponding period was calculated. Thus, cancer rates were reported as rates per 1,000 children per year with 95% CIs. The Poisson regression model, adjusted for age and correlated observation across time within the same patient, was used to compare cancer rates between the study periods. Survival analyses were performed using the Kaplan-Meier method with the log-rank test. Statistical analyses were performed using STATA, version 7.0 (STATA Corp, College Station, TX). P < .05 was considered statistically significant.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
From 1985 to 2004, 1,190 perinatally HIV-infected children were enrolled onto the Italian Register for HIV Infection in Children and never lost to follow-up. Median observation time was 8.06 years (range, 0.07 to 19.06 years), and total observation time was 10,037.66 years. Table 1 lists the characteristics of the study children.

Among the 264 children not observed from birth, the median age at first follow-up was of 4.19 years (range, 0.61 to 6.62 years). None of the children came to attention for HIV infection because they had cancer.

Cancers
Globally, 35 cancers occurred in 34 children from 1985 to 2004 (Fig 1). One child developed hepatoblastoma (5 years old) and was apparently cured after surgical resection and chemotherapy but developed a second cancer (NHL) 5 years later.

View larger version (20K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Age at cancer presentation of the study children. ALL, acute lymphoblastic leukemia; NHL, non-Hodgkin's lymphoma.

Nineteen children (54.3%) had severe (CD4⁺ T lymphocytes < 15%²) and four children (11.4%) had moderate (CD4⁺ T lymphocytes = 16% to 24%²) immunodeficiency at cancer onset, but notably, cancer also occurred in 12 children (34.3%) with a CD4⁺ T-lymphocyte percentage of more than 25%. In 19 patients with NHL, severe immune depletion was observed in 11 (57.9%) of 19 children. Two children (10.5%) had a moderate immunodeficiency, whereas six (31.6%) of 19 had CD4⁺ T-lymphocyte percentages of more than 25%.

Overall, 20 children (58.8%) with cancer died, with a mortality rate decreasing from 72.2% (16 of 22 children) before 1996 to 36.3% (four of 11 children) in 1996 to 1999 and to 0% (zero of two children) in 2000 to 2004 (P < .0001 by Kaplan-Meier analysis with log-rank test).

Characteristics and treatment of cancer patients diagnosed before year 2000 have been described in detail in our previous study.⁷ After year 2000, two cancers (one Kaposi's sarcoma and one NHL) occurred in two children age 1.1 and 14.9 years; their CD4⁺ T-lymphocyte values at cancer onset were 2% and 31%, respectively. Both children were off of antiretroviral therapy.

Children Lost to Follow-Up
One hundred forty-seven children (11.0%) were lost to follow-up. Median observation time was 2.69 years (range, 0.78 to 17.1 years), and total observation time was 607.42 years. One of these children developed Hodgkin's lymphoma in 1995 at the age of 6.8 years. The cancer rate in this population was 1.64 per 1,000 children per year (95% CI, 0.11 to 4.87 per 1,000 children per year; P = .285 v children never lost to follow-up). Repeating the analyses including children lost to follow-up, the differences in cancer rates among periods were confirmed (P = .344 for 1985 to 1995 v 1996 to 1999 and P < .0001 for 1985 to 1995 v 2000 to 2004).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
In the present study, cancer occurrences before and during the HAART era were analyzed in a large population of children with perinatal HIV infection. Cancer rates did not significantly change between the pre-HAART and the early HAART periods, whereas a striking reduction occurred after year 2000. Results were confirmed analyzing separately data from children observed from birth. Also, findings were unchanged when children lost to follow-up were included in the analysis.

The distribution of cancer diagnoses in our data set was similar to other reported pediatric series,^4,6,10-12 with lymphoid malignancies occurring most commonly. A relatively high frequency of vulvar carcinoma (n = 2) was observed. This finding is unusual for a pediatric data set, but because of the low number of patients, any conclusion at this time would be speculative. For the same reason, it was not possible to analyze changes in rates of individual cancers.

Our previous study on cancer occurrence⁷ provided detailed information on immunologic data and response to antiblastic treatment until 1999. Because two cancers occurred in the last time period, it was not possible to add more useful information at this point.

Whether the widespread use of HAART affects cancer occurrence in children is unclear.^2,6 As for other AIDS-related events, cancers may have been decreasing as a result of restored immunosurveillance.¹³ In adults, the incidences of Kaposi's sarcoma and primary CNS lymphoma have decreased sharply since 1996.¹⁴ Systemic NHL is also declining, although to a lesser extent, whereas the incidence of other cancers has not substantially changed.¹⁴ However, given the longer survival, HIV-related malignancies might become increasingly common. Recently, Biggar et al⁴ observed that primary brain lymphomas and leiomyosarcomas tended to occur in children surviving several years after AIDS onset. Our previous targeted study in Italian children until 1999⁷ did not observe variations in cancer rates before or after 1996. However, extending the observation period, a dramatic reduction in cancer rates was evident after year 2000. This finding might be a result of several, not exclusive factors. First, the HAART era is not a homogeneous period. The proportion of children receiving HAART increased by 20-fold from 1996 to 2004, and new potent antiretroviral drugs have been developing, improving the available therapeutic options. Second, time of exposure to HAART may also be an influence. In our population, the proportion of children taking HAART for at least 2 years increased 25-fold from 1996 to 2004. In a recent study,⁵ cancer incidence was higher in children with 2 years of HAART use than in children with more than 2 years of HAART, suggesting some protective effect, but there was no difference between children never receiving HAART and those receiving HAART for 2 years. Third, the prolonged follow-up period may be relevant. During the carcinogenesis process, there is a latency time between exposure to a specific risk factor and cancer onset. Thus, a long observation time may be necessary to reveal modifications in cancer rates.¹⁵ Finally, it must be considered that direct antitumoral properties of prolonged antiretroviral therapy have been suggested.^16,17

The reported cancer incidence in European children not infected with HIV is 0.14 per 1,000 children per year.¹⁸ Thus, the cancer incidence in HIV-infected children after year 2000, even if substantially reduced, remained about five-fold higher than in the general population.

Risk factors for pediatric HIV-related cancer have not been clarified yet. In a large study, neither route of infection nor zidovudine use were associated with cancer, and the association with high Epstein-Barr viral burden was present only in a subgroup of patients.¹² CD4⁺ T-lymphocyte count was a risk factor for cancer in one study⁵ but not in another.¹² In our study, approximately one third of children were not immune depleted at cancer onset.⁷ Also, analyzing separately data from children with NHL (which is typically associated with low CD4⁺ T-lymphocyte counts), severe immune depletion was observed in approximately half of the children. A functional defect, rather than a reduction in CD4⁺ cell count, might be responsible for the increased cancer risk. HAART, through the re-establishment of most of the T-cell functions,¹³ might be associated with restored immunosurveillance and reduced cancer risk. Interestingly, the two children who developed cancer after year 2000 were off of therapy.

Our survey was restricted to perinatally acquired HIV patients, and risk factor comparisons in the context of other studies including children infected with HIV across a wide age spectrum are difficult to interpret.^6,11,12 In our study, specialized pathology review was performed locally, and thus, potential misclassification of malignancy diagnosis without central pathology must be considered in interpreting our results. In conclusion, in our population, dramatically reduced cancer rates were observed in the late HAART period in parallel to the increasing proportion of children receiving HAART.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
The authors indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Elena Chiappini, Luisa Galli, Pier-Angelo Tovo, Maurizio de Martino

Provision of study materials or patients: Guido Castelli Gattinara, Giulio De Marco, Patrizia Osimani

Collection and assembly of data: Catiuscia Lisi, Carlo Giaquinto, Osvalda Rampon, Guido Castelli Gattinara, Giulio De Marco, Patrizia Osimani, Mariano Manzionna, Angela Miniaci, Carlo Pintor, Raffaella Rosso, Susanna Esposito, Alessandra Viganò, Icilio Dodi, Anna Maccabruni, Carlo Fundarò

Data analysis and interpretation: Elena Chiappini, Pier-Angelo Tovo, Clara Gabiano, Catiuscia Lisi, Carlo Giaquinto, Osvalda Rampon, Mariano Manzionna, Angela Miniaci, Carlo Pintor, Raffaella Rosso, Susanna Esposito, Alessandra Viganò, Icilio Dodi, Anna Maccabruni, Carlo Fundarò, Maurizio de Martino

Manuscript writing: Elena Chiappini, Luisa Galli, Pier-Angelo Tovo, Clara Gabiano, Maurizio de Martino

Final approval of manuscript: Elena Chiappini, Luisa Galli, Pier-Angelo Tovo, Clara Gabiano, Catiuscia Lisi, Carlo Giaquinto, Osvalda Rampon, Guido Castelli Gattinara, Giulio De Marco, Patrizia Osimani, Mariano Manzionna, Angela Miniaci, Carlo Pintor, Raffaella Rosso, Susanna Esposito, Alessandra Viganò, Icilio Dodi, Anna Maccabruni, Carlo Fundarò, Maurizio de Martino

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Participants: R. Cordiali (Ancona), D. De Mattia, G. Giannuzzo, C. Di Bari (Bari), M. Ruggeri (Bergamo), M. Masi, M. Ciccia, M. Lanari, F. Baldi (Bologna), L. Battisti (Bolzano), R. Badolato (Brescia), C. Dessì, M. Dedoni, M.L. Fenu, R. Cavallini (Cagliari), E. Anastasio, F. Merolla (Catanzaro), M. Sticca (Como), G. Pomero (Cuneo), T. Bezzi, E. Fiumana (Ferrara), F. Bonsignori, E. Sieni, L. Innocenti, P. Gervaso (Firenze), M.T. Cecchi (Forlì), C. Viscoli (Genova), M. Stronati (Mantova), A. Plebani, R. Pinzani, J. Bonjanin, A. Porta, N. Principi, V. Fabiano, G. Pattarino, V. Giacomet, F. Salvini, G.V. Zuccotti, M. Giovannini, G. Ferraris, R. Lipreri, C. Moretti (Milano), M. Cellini, M.C. Cano, P. Paolucci (Modena), E. Bruzzese, A. Guarino, L. Tarallo, F. Tancredi (Napoli), M. Pennazzato (Padova), E.R. Dalle Nogare, A. Sanfilippo, A. Romano, M. Saitta (Palermo), A. Barone (Parma), R. Consolini, A. Legitimo (Pisa), C. Magnani (Reggio Emilia), P. Falconieri, O. Genovese, A. Pantanella, A.M. Casadei, A. Martino, C. Concato, G. Anzidei, G. Bove, S. Cerilli, S. Catania, C. Ajassa (Roma), A. Ganau (Sassari), L. Cristiano (Taranto), A. Mazza, L. Gentilini (Trento), F. Mignone, C. Riva, C. Scorfaro (Torino), V. Portelli (Trapani), M. Rabusin (Trieste), A. Pellegatta (Varese), M. Molesini (Verona).

	NOTES

 
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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Submitted March 17, 2006; accepted October 5, 2006.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Chiappini, E. Articles by de Martino, M. Search for Related Content PubMed PubMed Citation Articles by Chiappini, E. Articles by de Martino, M. Social Bookmarking                            What's this?