Background

1. AIDS-related malignancies in teenagers horizontally infected with HIV-1 during infancyA.Cupşa¹, Florentina Dumitrescu¹, Irina Niculescu¹, L. Giubelan¹, Andreea Cristina Stoian¹, Amalia Romanescu², Cristina Iocu²¹University of Medicine and Pharmacy from Craiova, Romania, Infectious Diseases Department²“Victor Babes” Clinical Hospital of Infectious Diseases and Pneumology, Craiova, Romania

2. Background • HIV infection predisposes to several neoplastic conditions, especially non-Hodgkin lymphoma and Kaposi's sarcoma, and also intraepithelial cervical neoplasia, anal neoplasia [1,2] • For neoplasias associated with oncogenic human viruses, the role of HIV is most probably linked to its immunosuppressive effect and interference with immune-mediated tumour surveillance [2,3,4] ¹ Goedert, J. J., Cote, T. R., et al. (1998). Spectrum of AIDS-associated malignant disorders. Lancet351(9119), 1833–1839. ² Engels, E. A., Biggar, R. J., Hall, H. I., , et al. (2008). Cancer risk in people infected with human immunodeficiency virus in the United States. Int J Cancer123, 187–194. ³ Grulich, A., Wan, X., et al. (1999). Risk of cancer in people with AIDS. AIDS 13(7), 839–843. 4Schulz TF, Boshoff CH, Weiss RA HIV infection and neoplasia. Lancet. 1996 Aug 31;348(9027):587-91.

3. Objectives To assess : • the spectrum • prevalence • evolution of AIDS-related malignancies in teenagers horizontally infected with HIV-1 during their infancy

4. Material and methods • retrospective study, from 01.01.2000 to 31.12.2009, on a cumulative group of 594 adolescents (according to Tanner classification), born and horizontally infected with HIV-1 (mainly nosocomial) between 1988 and 1990, followed up by Regional Center for Evaluation and Monitoring of HIV/AIDS Infection, Craiova, Romania • Patients (Px) were clinically, biologically and imaging evaluated; diagnosis of certainty for malignant condition has been histopathologically established

5. Results-1 • 21 Px (3.5%) have been diagnosed with AIDS-associated malignancies, gender ratio M/F = 14/7 (66.7% / 33.3%) • mean age when malignancy has been diagnosed =15 [12; 18] years The spectrum and prevalence of malignancies: • 13 Px (61.9%)- non-Hodgkin lymphoma (NHL), of which: - 8 Px (38.2%)- diffuse large B-cell NHL - 2 Px (9.5%) - primary central nervous system lymphoma - 2 Px (9.5%) - Burkitt lymphoma - 1 Px (4.7%) – marginal zone B-cell NHL • 8 Px (38.1%) - Kaposi sarcoma

6. Results-2 • The average time between diagnosis of HIV infection and identifying neoplasia has been 6.3 [0; 15] years At the malignancy diagnosis: • average CD4 count =116.6 [9; 267] cells/mm³ • average HIV-RNA = 5.45 [3.89; 5.89] log10 copies/ml • 11 Px (52.4%) were antiretroviral multiexperienced, 4 other Px (19%) were naïve (neoplasia highlighted HIV infection) • All Px received ARTc, while chemotherapy courses has been introduced in Px diagnosed with lymphoma

7. Evolution • 12 deaths (57.2%) – 11 lymphoma Px, one case of Kaposi sarcoma (also having concomitant pulmonary tuberculosis) - with an average survival time after diagnosis of 5.6 [1; 14] months • 2 Px (9.5.%) with NHL demonstrated remission • 7 Px (33.3%) with Kaposi sarcoma, treated only with ARV, were still alive after an average of 5.4 [1; 9] years of follow-up.

8. Cases presentations

9. N.A, female, born in 1989 Late diagnosis of HIV infection in March 2008 (long term non progressor?) with a concomitant diagnosis of palatinal Kaposi sarcoma CD4 count=18 cells/mm³ HIV-RNA= 28.800 c/ml ARTc - 2NRTI+PI/r (no chemotherapy) August 2008: CD4=217 cells/mm³ HIV-RNA< 50 c/ml Complete remission of the sarcoma Case 1: Kaposi Sarcoma

10. D.N. female, born in 1990 Diagnosed with HIV infection in 1996, EBV-Ig G anti EBNA, anti VCA-positives Burkitt lymphoma in 2001 When malignancy has been recognized: CD4= 152cells/mm³ ART: 2 NRTI - 1997 NNRTI+PI since 2000 Case 2: Burkitt lymphoma

11. The ARTc regimen has been changed: 2 NRTI+PI/r She has received chemotherapy - CHOP (cyclophosphamidum-doxorubicinum-oncovin/vincristinum-prednisonum) regimen (photo has been taken after the first chemotherapy course) She died 6 months later due to renal failure Case 2: Burkitt lymphoma

12. Case 3: Burkitt lymphoma • D.F, male, born in 1988 • Diagnosed with HIV infection -1993, EBV-Ig G anti EBNA, anti VCA-positives, ART since 1996, 2 NRTI+PI since 2002 • CD4 count=632 cells/mm³-Feb.2006 • Diagnosed with Burkitt lymphoma in May 2006 – mandibulartumour (CD4=212cells/mm³) • Only 4 months survival (mandibular, axilar, iliac tumours, medular invasion)

13. Case 3: Burkitt lymphoma

14. V.I, female, born in 1989, diagnosed with HIV infection in 1996 ART since 1996, 2 NRTI+PI/r since 2007 May 2008: CD4=431cells/mm³, HIV-RNA <50 copies/ml marginal zone B-cell NHL in August 2008 Case 4: Marginal zone B-cell NHL

15. Case 4:Marginal zone B-cell non-Hodgkin lymphoma

16. Case 4: Marginal zone B-cell NHL • Px starts radiation, but after two courses the swelling, which has had an initial tendency to remission, shows progression • CT proves the presence of two intraconjunctival abscesses; • lymphoma continues to progress and breaches the anterior right eye pole, requiring enucleation

17. Case 4: Marginal zone B-cell NHL • A new CT exam rises suspicion of intracranial expansive formations in the frontal right lobe. Reassessment of CD4 lymphocytes shows their fall in (the new value at 148 cells/mm³) • The Px died in October 2008 • The case shows the fulminating progression of malignant lesions in a special host (previously stabilized in terms of clinical, immunological and virological aspects) and the rapid and profound impact on cellular immunity

18. D.N.. Male, born in 1988 Diagnosed with HIV infection in 1996 ART since 1996 Diagnosed with diffuse large B cell NHL in 2001 Chemotherapy: - COMP (cyclophosphamidum-oncovin/vincristinum -methotrexatum-prednisonum) regimen-18 months Case 5: NHL

19. Case 5: Large B cell non-Hodgkin lymphoma with nuclear pleomorphism and vascular invasionHematoxylin-eosin stain, x 20 optical enlargement

20. Evolution, May 2008: Averagewell-being, BMI = 19 kg/m², oral thrush CD4 count =71cells/mm³, HIV-RNA=31.400 c/ml, TG=367mg/dl A genotypic test has been performed and the following mutations have been revealed: RT mutation-D67N, T69D, V75T, M184V, T215F, K219Q; PR mutation- L10V, K20R, L24I, L33F, M36I, M46I, I50V, I54V, V77I, V82A

21. Taking into account the results of the genotypic test and considering the fact that the Px has been exposed, during 1999-2001, to NNRTI (with a subsequent clinical, immunological and virological failure due, probably, to the occurence of NNRTI resistance), the following regimen has been proposed: RAL + T20 + DRV/r After 12 months it is noted: Two minor episodes of respiratory infections, not requiring hospitalization A good immune reconstruction (CD4 count 384 cells/mm³) HIV-RNA undetectable (< 50 copies/ml after one month of treatment with the new regimen)

22. Due to adverse effects of T20 (occurence of subcutaneous nodules), a new regimen has been introduced: ABC + 3TC +RAL+DRV/r In August 2009: BMI = 23.7kg/ m² CD4 count =541 cells/mm³ HIV-RNA<50 copies/ml no signs of opportunistic diseases without relapses of NHL following hypolipemiant treatment maximal well-being and with social integration (student)

23. CD4 evolution Cells/mm³ ABC+3TC+LPV/r AZT ABC+3TC+RAL+DRV+RTV AZT+ddc IDV+EFV d4T+3TC+IDV+RTV d4T+ddI+APV+RTV T20+RAL+DRV+RTV

24. HIV-RNA evolution

25. Conclusions • in HIV-1 positive teenagers horizontally infected during infancy, AIDS-related malignancies have a relatively low prevalence • when present, they are accompanied by an increased mortality in spite of appropriate diagnosis and treatment.

26. Acknowledgement: D. Rodica Costa-Timişoara D.Polixenia Stancu D. Luminţa Ocroteală D. Elena Ioniţă D. Surugiu Paula D. Volosciuc Elena D. Marinescu Maria D. Georgescu Adriana D. Lucia Godeanu D. D. Ecobici Psychologist Liliana Marinescu Nurses Patients and their family Thank you for your attention!