1. HIV Associated Malignancies Amanda Peppercorn, M.D. Assistant Professor of Medicine Division of Infectious Diseases

2. Overview • HIV associated malignancies • Indicator condition in AIDS • Interplay with oncogenic viruses • Epidemiology • Diagnosis • Therapy

3. Case #1 • HPI: 73 yo CM, Yale professor, no significant pmhx • Jan 2003- complained of fatigue to PCP, routine labs showed new anemia with Hct 32% and platelets 110K • Extensive evaluation by Heme/onc over next several months including bone marrow bx unrevealing except for abd u/s showed splenomegaly and he was diagnosed after extensive GI eval with “cryptogenic cirrhosis” even though no evidence of liver pathology, portal HTN or liver synthetic dysfunction • November 2003- episode of left thoracic zoster, self resolves

4. May 2004- develops new left facial palsy, treated for HSV and Lyme cranial neuritis (despite negative Lyme antibody) with steroids, valtrex and doxycycline with improvement in sx • July 2004- facial palsy returns and over 1-2 weeks is noted by son to be confused • August 2004- develops lethargyobtundation and is admitted to OSH where Brain MRI shows new peri-ventricular rim enhancing lesion with mass effect • HIV antibody finally sent and is positive • LP done after administration of steroids • +EBV PCR, +atypical lymphocytes c/w Primary CNS Lymphoma • CD4 70, Viral load 75K

5. Patient treated with Combivir and Sustiva with good virologic response • Required neupogen and erythropoitin throughout cancer treatment course • Lymphoma treated with IT methotrexate, steroids and whole brain XRT with regression • Complicated by febrile neutropenia • Complicated by severe perianal HSV outbreak • Patient’s neurologic status completely improved

6. Historical Time-line • March 1981: First report of 8 cases of Kaposi’s sarcoma among MSM in SF and NY • June 1981: MMWR reports 5 cases PCP in previously healthy young MSM in LA, 2 died • 1982: phrase “AIDS” coined, first 4 cases NHL reported • 1983: Primary CNS lymphoma (PCNSL) described • 1984: viruses “LAV” (lymphadenopathy associated virus) and HTLV-III isolated • 1985: Non-Hodgkins Lymphoma added to KS and PCNSL by CDC as AIDS-defining condition • 1986: LAV/HTLV-IIIHIV • 1993: Cervical carcinoma added as ADC

7. AIDS Defining Malignancies (ADMs) • KS • Lymphoma: PCNSL, Immunoblastic, Burkitt’s, Primary Effusion • Cervical carcinoma • Up to 40% of HIV+ pts had an ADM in the pre-HAART era • After PCP, malignancy was most frequent OI

8. Decline in KS, NHL, proportional to CD4 count Non-ADMs > ADMs in overall morbidity/mortality Cancer accounts for approx 30% deaths in HIV+ currently Traditional RFs: smoking, etoh, viral co-infections Non-ADMs with greater frequency in HIV+(SIR=standardized incidence ratio): Anal (HPV), SIR 19.6 Lung (tobacco), SIR 2.6 Hodgkin’s disease (EBV), SIR 13.6 Liver (HBV, HCV, etoh), SIR 3.3 Head/neck (tobacco, etoh, HPV), 2.2 Melanoma, other skin cancers (SCC, merkel cell, BCC) MM, SIR 2.2 Leukemia, SIR 2.2 Brain CA, gastric, renal, testicular (seminoma) HAART Era

9. Oncogenic Virus Association

10. Pathogenesis • Similar risk as seen in transplant recipients who experience 100-fold increased risk of cancer (renal, SCC, NLH, KS, uterine, cervic, vulva, sarcoma) • Loss of immune surveillance of tumor cells • ?Role of HIV genes in oncogenesis (esp as growth factors)

11. KS • Low grade soft tissue sarcoma, vascular • Low CD4 • HHV-8 (KSHV) • Skin (predominant) • Visceral: bronchus/lung, GI tract, liver, oral • Treatment: HAART, XRT, anthracyclines, paclitaxel, pegylated interferon, laser or cryotherapy • IRIS

12. KS on heel of immunocompromised patient Images courtesy of Dr. Stephen Tabet.Nicodemus M et al. HEPP News (Brown Medical School), August/September 2001.

13. TIS Staging Classification

14. NHL • 70-90% High grade B cell lymphomas (large B cell, immunoblastic, Burktt’s—c-myc translocation) • PCNSL—15% • Primary Effusion Lymphoma (“Body Cavity Lymphoma”)—rare

15. NHL • Present at more advanced stage, extranodal disease (GI tract common), bone marrow, liver and lung, CNS, 80% Stage 4 disease at presentation • More often with “B” sx—night sweats, fever, weight loss • Incidence inversely related to CD4 count but can occur at any CD4 • Diagnosis same as in non-HIV pt but higher rate of asymptomatic CNS involvement • FNA usually not adequate, need excisional BX

16. NHL Treatment • Optimal therapy not defined: • Standard first line therapies (CHOP) not as effective or durable in HIV population (increased expression of MDR-1 gene) • IT methotrexate or ara-C • HAART definitely improves survival • 50-60% response rate • High rate of OI complications • Alternative regimens: EPOCH, M-BACOD • No good second line regimens, BMT not an option currently

17. HAART with Chemotherapy • Burkitt’s Retrospective study of Hyper-CVAD +/- HAART [Cortes, Cancer 2002] • 6/7 on HAART CR, 4/4 no HAART died • Large B cell Lymphoma Retrospective study of CHOP-HAART (24 pts) versus CHOP (+/- AZT mono, 80 pts)[Vaccher, Cancer 2001] • OI: 18 v 52% • Survival: long term survival versus medium 7 months

18. HAART and Chemotherapy • PI v NNRTI based regimen equivalent • Some anti-neoplastic effect of AZT and PIs • Need to implement OI prophylaxis with low CD4 counts in setting of bone marrow suppression • Mucositis, chemo related n/v can inhibit oral intake of ARVs • IL-6 inhibitors under investigation • Role of rituximab unclear; marked increased death rate due to infection [Kaplan, Blood 2005]

19. Primary Effusion Lymphoma • Rare • HHV-8 • Serous effusions (pleural, peritoneal, pericardial, joint effusions) with malignant lymphocytes • No mass lesions • CHOP + HAART • Very poor prognosis

20. PCNSL • EBV • 100-1000x higher than general population • CD4<100, usually <50 • Dx: LP +EBV, MRI with homogeneous, sometimes ring enhancing lesions, often peri-ventricular, often +mass effect, Thallium SPECT with early uptake • Tx: whole brain XRT + steroids +/- IT methotrexate • Prognosis: poor in pre-HAART era, overall still very poor

21. Hodgkin’s Lymphoma and HIV • Usually advanced stage at time of diagnosis (stage 3,4) • More extra-nodal involvement—bone marrow, liver • Worse prognostic cell type—mixed cellularity histologic subtype (nodular schlerosis most common in non-HIV) • Worse overall prognosis • Better outcomes in era of HAART

22. Cervical Cancer • Co-infection with HPV • Earlier age with advanced disease • Paps recommended twice a year at time of HIV dx; if normal, can screen every year • Dx, Management same as in non-HIV population • No relation to CD4 count

23. % HIV prevalence, adult (15-49) Global HIV epidemic, 1990‒2005 Number of people living with HIV (millions) % HIV prevalence, adult (15‒49) • 38.6 million living with HIV [33 to 46 million] • 24.5 million in SS Africa • [21.6 to 27.4 million] • 4.1 million new infections [3.4 to 6.2 million] • 2.8 million deaths[2.4 to 3.3 million] 50 5.0 40 4.0 30 3.0 20 2.0 10 1.0 0 0.0 1990 1995 2000 2005 Number of people living with HIV Bar indicates the range around the estimate Source: UNAIDS 2006

24. Children • Leiomyosarcoma (?EBV) • NHL • Cervical, thyroid/ lung • KS • Burkitt’s

25. ADMs in Developing Nations • KS in Africa (men and women) • NHL (less than developed nations) • Cervical cancer (unclear how HIV has impacted) • SCC of the conjunctiva (?HPV) • Related to sun exposure • Risen over past 30 years in Ss Africa • 10 fold higher in HIV+

26. Case #2 • 60 yo woman w longstanding HIV c/b:HIVAN on HD, remote PCP, remote GB • HAART regimen: abacavir, efavirenz, atazanavir, ritonavir with excellent CD4 and virologic suppression • Routine mammogram: 8 cm left breast mass with enlarged left axillary mass

27. Work up: T2N2M0 disease “locally advanced” due to +LN • Well differentiated, ER+, PR-, Her-2- • Treated with “dose-reduced” neoadjuvant Taxol alone due to “co-morbidities” • Taxol tolerated well except for diarrhea and alopecia • Followed by radical modified mastectomy which showed poor response to chemo with 3 cm residual disease • CD4 drop from 800 to 150, dapsone initiated

28. Oncologist starts pt on Tamoxifen • Seen in HIV clinic • Tamoxifen metabolism made completely unpredictable by ritonavir • Recommendation made to oncology to use Arimidex instead of Tamoxifen for more reliable anti-tumor effect • Seen recently in clinic for CA-MRSA gluteal abscess and bacteremia

29. Lessons • Screen: PSA, mammogram, cervical (anal) pap, colonoscopy, yearly CXR in smokers, AFP/liver imaging in HBV and ESLD/cirrhosis/HCV • ADVOCATE! • Check HAART drug interactions with chemotherapy and make necessary modifications • Try to maintain full chemo and full HAART • Monitor carefully for infectious complications, need to implement OI prophylaxis • Emerging data that HAART + high CD4 count renders pt outcomes to general cancer treatment equivalent to non-HIV+ population

31. EuroSIDA: Reduction in the incidence of AIDS and death since the introduction of HAART Morbidity and mortality across Europe, Israel and Argentina ~ 10,000 patients 100 100 % patients on HAART Combined rate of AIDS and death 80 60 Combined AIDS and death rates % Patients 10 40 20 0 1 Sept 1994 Sept 1999–March 2000 Sept 2000–March 2001 Sept 1998–March 1999 March 1998–Sept 1998 March 1995–Sept 1995 Sept 1995–March 1996 March 1996– Sept 1996 Sept 1996–March 1997 Sept 1997–March 1998 M<arch 1995 March 1997–Sept 1997 March 2000–Sept 2000 Sept 2001–onwards March 2001– Sept 2001 March 1999– Sept 1999 Mocroft A. et al, Lancet 2003; 362: 22–29