HIV Associated Malignancies

HIV Associated Malignancies Amanda Peppercorn, M.D. Assistant Professor of Medicine Division of Infectious Diseases University of North Carolina 8/11/2008 Overview  HIV associated malignancies • Indicator condition in AIDS • Interplay with oncogenic viruses • Epidemiology  Diagnosis  Therapy University of North Carolina 8/11/2008 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 University of North Carolina 8/11/2008  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 periventricular 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 University of North Carolina 8/11/2008  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 University of North Carolina 8/11/2008 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 8/11/2008 University of North Carolina 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 preHAART era After PCP, malignancy was most frequent OI 8/11/2008 University of North Carolina HAART Era  Decline in KS, NHL,  Non-ADMs with greater proportional to CD4 count frequency in HIV+(SIR=standardized incidence ratio):  Non-ADMs > ADMs in • Anal (HPV), SIR 19.6 overall • Lung (tobacco), SIR 2.6 morbidity/mortality  Cancer accounts for approx 30% deaths in HIV+ currently  Traditional RFs: smoking, etoh, viral co-infections University of North Carolina • • • • 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) 8/11/2008 Oncogenic Virus Association Virus Hepatitis B Malignancy Hepatocellular carcinoma Hepatitis C EBV HPV HHV-8 (KSHV) Hepatocellular carcinoma NHL, Hodgkins disease, Primary CNS lymphoma, nasopharyngeal carcinoma Cervical, Anal, Head and Neck Kaposi’s sarcoma, Primary Effusion Lymphoma (Body Cavity Lymphoma) University of North Carolina 8/11/2008 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) 8/11/2008 University of North Carolina 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 8/11/2008 University of North Carolina KS on heel of immunocompromised patient University of North et al. HEPP News (Brown Medical School), August/September 2001. 8/11/2008 Nicodemus M Carolina Images courtesy of Dr. Stephen Tabet. TIS Staging Classification Good Risk Tumor, T T0: confined to skin and/or LNs or minimal oral dx I0: CD4>200 Poor risk T1: tumor associated edema or ulceration, extensive oral KS, GI KS, other non-nodal viscera CD4< 200 Immune System, I Systemic illness, S S0: no hx OI or thrush, no S1: hx OI or thrush, ―B‖ B sx, Karnofsky score>70 sx, karnofscky performance score<70, other HIV related illness (ex lymphoma, neurologic) 8/11/2008 University of North Carolina NHL    70-90% High grade B cell lymphomas (large B cell, immunoblastic, Burktt’s—cmyc translocation) PCNSL—15% Primary Effusion Lymphoma (―Body Cavity Lymphoma‖)—rare University of North Carolina 8/11/2008 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 University of North Carolina 8/11/2008 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 University of North Carolina 8/11/2008 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 University of North Carolina 8/11/2008 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] 8/11/2008 University of North Carolina Primary Effusion Lymphoma       Rare HHV-8 Serous effusions (pleural, peritoneal, pericardial, joint effusions) with malignant lymphocytes No mass lesions CHOP + HAART Very poor prognosis 8/11/2008 University of North Carolina PCNSL       EBV 100-1000x higher than general population CD4<100, usually <50 Dx: LP +EBV, MRI with homogeneous, sometimes ring enhancing lesions, often periventricular, 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 8/11/2008 University of North Carolina 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 8/11/2008 University of North Carolina 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 8/11/2008 University of North Carolina Global HIV epidemic, 1990‒2005 Number of people living with HIV (millions) 50 40 % HIV prevalence, adult (15‒49) 5.0 4.0 • 38.6 million living with HIV [33 to 46 million] 30 20 3.0 2.0 • 24.5 million in SS Africa [21.6 to 27.4 million] 10 0 1990 1995 2000 2005 1.0 0.0 • 4.1 million new infections [3.4 to 6.2 million] • 2.8 million deaths [2.4 to 3.3 million] Number of people living with HIV % HIV prevalence, adult (15-49) Bar indicates the range around the estimate University of North Carolina Source: UNAIDS 2006 8/11/2008 Children      Leiomyosarcoma (?EBV) NHL Cervical, thyroid/ lung KS Burkitt’s University of North Carolina 8/11/2008 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+ University of North Carolina 8/11/2008 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 8/11/2008 University of North Carolina       Work up: T2N2M0 disease ―locally advanced‖ due to +LN Well differentiated, ER+, PR-, Her-2Treated 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 8/11/2008 University of North Carolina  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 University of North Carolina 8/11/2008 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 University of North Carolina 8/11/2008 University of North Carolina 8/11/2008 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 Combined AIDS and death rates 100 % patients on HAART Combined rate of AIDS and death 100 80 % Patients 60 10 40 20 1 0 Mocroft A. et al, Lancet 2003; 362: 22–29 University of North Carolina 8/11/2008