HIV and cancer
Mark Bower ESCMID eLibrary © by author People living with cancer and HIV
Adults and children living with HIV in 2015
Total prevalence: Total prevalence: ESCMID32.5 million eLibrary36.7 million © by authorData from CRUK and UNAIDS People dying from cancer and HIV
Estimated deaths from cancer Estimated deaths from AIDS in in 2012 2015
ESCMID8.2 million deaths eLibrary1.1 million deaths © by authorData from CRUK and UNAIDS AIDS defining malignancies
Malignancy Virus
Kaposi’s sarcoma KSHV
Non-Hodgkin’s lymphoma (including primary cerebral EBV lymphoma) CervicalESCMID cancer eLibraryHPV © by author Kaposi sarcoma timelines
1872 Moritz Kaposi describes skin sarcoma in Vienna
ESCMID eLibrary © by author Austro-Hungarian Empire 1872
Kaposvar
ESCMID eLibrary © by author Cases of PCP in 1981 5 June
ESCMID eLibrary © by author One month later.....KS
RARE CANCER SEEN IN 41 HOMOSEXUALS By Lawrence K Altman 3 July 1981 ESCMID eLibrary © by author Rock Hudson died in October 1985.... and everyone took notice of AIDS
ESCMID eLibrary © by author 1993 Tom Hanks gets KS
ESCMID eLibrary © by author KS lesions
ESCMID eLibrary © by author Kaposi sarcoma Most common cancer in people living with HIV
Accounts for 27%, 35% & 24% of all cancers in Uganda, Zimbabwe & Mozambique respectively
ESCMID eLibrary © byPhilos Transauthor R Soc Lond B Biol Sci. 2001;356:517-34. Dame Valerie Beral & Harold Jaffe
Kaposi's ESCMID sarcoma among persons with AIDS: eLibrary a sexually transmitted infection ? Lancet 1990; 335: 123-8. © by author HHV8 (KSHV) discovery
1994 Novel herpesvirus sequences from KS lesions Patrick Moore & Yuan Chang
ESCMID eLibrary © by author KSHV (HHV8) Kaposi sarcoma herpesvirus (KSHV)
or
Human ESCMID eLibraryherpesvirus 8 (HHV8) © by authorChang Y et al., 1994 KSHV family tree Gammaherpesviruses Rhadinovirus HVS EHV-2 KSHV EBV Alphaherpesviruses Lymphocryptovirus HVS-1 HVS-2
EHV-1 PRV
VZV
HHV-7 0.2 Divergence ESCMIDHHV-6 eLibrary CMV Betaherpesviruses © by author Robert Koch (Nobel prize in 1905)
ESCMID eLibrary © by author Koch's postulates 1. Present in every case of the disease
KSHV infects spindle cells in KS lesions (all types) ESCMID eLibrary © by author Koch's postulates 2. Isolate organism from a patient with the disease and grow in culture KSHV grown from a cell line derived from patient with pulmonary ESCMID eLibraryKS © by author Koch's postulates 3. Infection precedes and predicts illness
100 KSHV absent at 75 time zero
50
KSHV 25 present at time zero
KS of free remaining Percentage ESCMID eLibrary 0 0 12 24 36 48 60 72 ©Time (mo) by authorWhitby et al. Lancet 1995;346:799 KSHV Transmission
ESCMID eLibrary © by author HHV8 Transmission HHV8 prevalence & number of partners
ESCMID eLibrary Martin JN et al., 1998 © by author HHV8 Transmission
HHV8 Prevalence in Uganda by age
ESCMID eLibrary © by authorInt J Cancer. 1998; 77: 817-20. What is sex?
Non-sexual horizontal transmission
Highest levels in saliva
ESCMID eLibrary Mayama S et al., 1998 © by author KSHV genome
ESCMID eLibrary Antman K and Chang Y. NEJM 2000 342 1027© - 1038 by author The Hallmarks of Cancer (2011)
ESCMID eLibrary © by author KSHV oncogenes
ESCMID eLibrary © by author Kaposi sarcoma histology
Spindle cells of Kaposi sarcoma
Extravasated red cells
KSHV immunostain showing virus presence in KS spindle ESCMID eLibrarycells © by author KS spindle cell origin
ESCMID eLibrary © by author Immunity & risk of KS
250
200 The risk of KS 150 correlates with CD4 cell count
100 Relative risk Relative
50
0 >200 100–199 0–99 ESCMIDCD4 count eLibrary © by author Emergence of cART in late 1990s
ESCMID eLibrary © by author KS incidence fell KS incidence rates 1992-6 vs 1997-9
ESCMID eLibrary International Collaboration on HIV and Cancer, 2000 © by author cART prevents KS
ESCMID eLibrary © by authorAIDS 2003, 17: 17 cART healing KS (3m apart)
ESCMID eLibrary © by author cART alone causes regression of KS
1 80% don’t need any 0.8 other treatment for
0.6 T0 stage KS over 10 years of follow-up
0.4 Cum. DFsurvival Cum.
0.2
n = 163 0 ESCMID0 2 4 6 8 10 eLibrary12 14 Years AIDS 2009;23 (13):1701–6 © by author Non-Hodgkin Lymphoma
ESCMID eLibrary © by author The lymphoma lottery
60-100 fold increase in incidence of NHL in people living with HIV/AIDS
ESCMID eLibrary © by author Lymphoma in PLWH
• High grade systemic B cell NHL – Systemic NHL – Plasmablastic lymphoma & PEL • Primary cerebral lymphoma
• Hodgkin lymphoma ESCMID eLibrary © by author The lymphoma lottery
Immuno- HIV Other risk suppressi factors on
HAART ESCMID eLibrary Non-Hodgkin Lymphoma © by author Conventional Virology of lymphoma in risk factors PLWH Histological subtype EBV+ KSHV+
Burkitt lymphoma (DL) 60% 0%
Diffuse large B-cell lymphoma (DLBCL) 90% 0%
Extra-cavity primary effusion lymphoma 90% 100%
Primary effusion lymphoma (PEL) 90% 100% Plasmablastic ESCMIDlymphoma (oral type) 80% eLibrary0% Plasmablastic lymphoma (associated 0% 100% with MCD) © by author CD4 and risk of NHL Immuno- suppression 250
200
150
100 Relative risk Relative
50 Risk of lymphoma 0 >200 100–199 0–99 rises as CD4 falls ESCMIDCD4 count eLibrary © by authorJNCI 2000, 92:1500 Lymphoma: HIV vs transplants HIV
Both NHL and HD are more common in HIV than ESCMIDtransplant recipients and BL iseLibrary only associated with HIV not transplantation © by author cART prevents NHL cART
No ARV history
NA only
PI and NA HAART NNRTI and NA
NNRTI and PI and NA
0 0.2 0.4 0.6 0.8 1 1.2 1.4 ESCMIDRate ratio of NHL incidence eLibrary JCO 2004;22:2177 © by author Diffuse large cell Burkitt’s lymphoma lymphoma ESCMID eLibrary © by author Pathogenesis of HIV associated DLBL
Advanced HIV, low CD4 count Loss of immune surveillance Proliferation of EBV+ latency 3 lymphoid cells
ESCMID eLibrary © by author Pathogenesis of HIV associated BL Early HIV, high CD4 B cell proliferation Immunoglobulin gene rearrangement error
ESCMID eLibrary © by author Lymphomas in PLWH at CWH by decade
100%
90%
80%
70% Low grade T-cell 60% PEL 50% Plasmablastic
40% Burkitt Hodgkins 30% DLBCL 20% PCL
10%
ESCMID0% eLibrary 1986-1995 1996-2005 2006-2015 Axis Title © by author All HIV associated lymphomas (n=615)
1
.8
.6 2006-2015
.4 1996-2005
Cum.Survival
.2
0 1986-1995 ESCMID0 5 10 15eLibrary20 25 30 Years © by author Burkitt Lymphoma: (R)-CODOX-M/IVAC
Overall Survival
1.0
N=94
0.5 Fraction survival Fraction
0.0 ESCMID0 50 100 eLibrary150 Time (Months) © by author DLBCL overall survival with R-CHOP
100 Overall survival according to HIV status
80 Log rank p = 0.03 HIV+ (n=97; dead=19) 60 HIV- (n=208; dead=77)
40 Overall Survival Overall
20
0 ESCMID0 20 40 60 80 eLibrary100 120 Time (months) © byCoutinho authorR, AIDS. 2014; 28: 689-697 “A world without AIDS”
ESCMID eLibrary © by author AIDS defining malignancies in USA 1991–2005 10% over 50 yrs 40% over 50 yrs 8000 7000 60 years and older 50-59 years 7000 6000
40-49 years years - 6000 30-39 years 20-29 years 5000 13-19 years 5000
0-12 years 4000 defining cancers cancers defining - 4000 3000 3000 2000 2000
Number of AIDS of Number 1000 1000 Incidence rate per 100,000 person 100,000 per rate Incidence
ESCMID0 eLibrary0
1991
1993 1994 1998 1999
2003 1995
1997
1992 2002
1996 2004 2005
2000 2001 Adapted from Shiels MS et al. J Natl Cancer Inst. 2011;103:753 ©-62. by author START Trial: an oncologist’s view
Endpoint Immediate Deferred Hazard P value initiation group initiation group ratio (n=2326) (n=2359)
N /100 py N /100 py KS 1 0.01 11 0.16 0.09 p=0.02 Lymphoma ESCMID3 0.04 10 eLibrary0.14 0.30 p=0.07 © by authorNEJM 2015, 373(9):795-807 NADM in older PLWH
1991 2003 20% of cancers in 60% of cancers in over 50 yrs over 50 yrs
2500 800
2250 700 60 years and older 2000 600
50-59 years 1750 years
40-49 years 500 - 1500 30-39 years 400 20-29 years 1250 13-19 years 1000 300
0-12 years defining AIDS cancers
- 750 200 500 100 250
0 0
Number nonof
Incidence Rate per 100,000 IncidencePerson Rate
1992 1997 2000 2005 1993 1994 1995 1996 1998 1999 2001 2002 2003 2004 ESCMID1991 eLibrary Adapted from Shiels MS et al. J Natl Cancer Inst. 2011;103:753 ©-62. by author D:A:D More deaths from NADM
Cause of death 1999-2000 Cause of death 2009-2011
8% 20%
92% 80%
ESCMIDNADM Other causes eLibraryNADM Other causes © by authorWorm SW, BMC Infect Dis. 2013; 13: 471 Cancer: UK Age-Specific Incidence Rates 2010
ESCMID eLibrary © by authorData from CRUK Age distributions: HIV/AIDS and general populations
More cancers Different cancers
ESCMID eLibrary © by authorAnn Intern Med. 2010;153(7):452-460 Most common cancers by age
25-49 years 50-74 years Men Testis cancer Prostate cancer Melanoma Lung cancer Colorectal cancer Colorectal cancer
Women Breast cancer Breast cancer Melanoma Lung cancer Cervical cancer Colorectal cancer ESCMID eLibrary ©Bower Mby and Waxman J.author Lecture notes: Oncology, 3rd Edition. 2015 Cancers in people living with HIV (CWH 1985-2015)
Cancers 2738
ADM NADM 2056 (75%) 682 (25%)
KS NHL Cervical ESCMID1537 (56%) 517 (19%) eLibrary2 (0.1%) © by author The spectrum of NADM at CWH: 431 cases
94% male Mean age 48 years Median CD4 cell count 379/mm3 75% were on cART ESCMID86% on cART had an eLibrary undetectable VL © by authorHIV Medicine 2013, 14 (suppl 2) 27 Head and Melanoma Hepatocellular Colorectal cancer neck cancer 4% cancer 4% 4% 4% Germ cell Hodgkin tumour lymphoma 5% 23% Prostate cancer 6% Lung cancer Anal cancer 11% 21% Non-melanoma skin cancer 18%
Oncological ESCMID viruses and bacteria eLibrary could account for up to 263 (61%) of these NADM. © by authorHIV Medicine 2013, 14 (suppl 2) 27 NADM with raised SIRs & infectious cause NADM Cases SIR Infectious cause Hodgkin’s 802 11 EBV Liver 133 5.2 Hep B & C Gastric 89 1.9 H pylori Anal 303 29 Vulva 21 6.5 Penis 21 4.4 Skin (NMSC) 121 4.1 Lip 30 2.8 HPV Larynx 142 2.7 Oral 238 2.3 Eye ESCMID11 1.9 eLibraryGrulich et al. Oesophagus 48 1.6 Lancet. 2007, 370:59-67 SIR = standardized incidence ratio© by author The seven human cancer viruses
Year Virus 1964 Epstein-Barr virus Epstein et al. Lancet 15, 702-703 1965 Hepatitis B virus Blumberg et al. JAMA 191, 541-546 1980 HTLV I Poiesz et al. PNAS 77, 7415-7419 1980 High-risk human papillomavirus Poiesz et al. PNAS 77, 7415-7419 1989 Hepatitis C virus Choo et al. Science 244, 359-362 1994 Kaposi’s sarcoma Herpesvirus Chang et al. Science 265, 1865-1869 2008 Merkel cell polyomavirus Feng et al. Science 319, 1096-1100 20% ofESCMID cancer cases worldwide caused eLibrary by infection, 10-15% by viruses
Parkin DM, Int J Cancer 2006;118:3030-44 © by author Non-infectious NADM with raised SIRs
NADM Cases SIR Leukaemia 235 3.2 Lung 1016 2.7 Myeloma 76 2.7 Brain 192 2.2 Kidney 93 1.5 Testis 216 1.4 ESCMIDMelanoma 200 eLibrary1.2 © byGrulich author et al. Lancet. 2007, 370:59-67 NADM: Epidemiological summary
The risk of most NADM is unrelated to CD4+ T-cell count The risk of most NADM rises with age Overall the incidence of NADM is not declining despite cART ESCMID eLibrary 1. Grulich et al. Lancet. 2007;370:59 –67, 2. Shiels MS et al. J Natl Cancer© Inst 2011;103(9):753 by–62 author NADM: Treatment summary
Outcomes are similar in HIV+ and HIV- people if the treatment is the same
As long as the HIV is diagnosed and treated too
Attention to drug interactions and OI prophylaxis ESCMID eLibrary
OI, opportunistic infection HIV Med 2014;15 Suppl 2:1 –92 © by author Drug interactions?
Antiretrovirals
Chemotherapy
ESCMID eLibrary © by author Strong inhibitors of CYP3A4
>80% decrease in clearance or >5 fold rise in AUC
Protease inhibitors (ritonavir & cobicistat) Macrolide antibiotics (clarithromycin) Azole antifungals (ketoconazole, itraconazole) ESCMID eLibrary © by author CYP3A4 cytotoxic substrates
Anthracyclines Vinca alkaloids Topoisomerase inhibitors (etoposide & irinotecan) Taxanes Sorafenib, sunitinib, vemurafenib, gefitinib, ESCMIDerlotinib, temsirolimus eLibrary, imatinib……. © by author Effects of chemotherapy on CD4 & VL
300
250
200 On average CD4 falls by 150 50% but no change in
100 plasma HIV viral load Mean CD4 count/ml CD4 Mean 50
Chemotherapy
CD4 pre CT pre CD4
CD4 3m on CT on 3m CD4
CD4 1m on CT on 1m CD4
CD4 3m post CT post 3m CD4 CT post 6m CD4 ESCMIDCT post 1m CD4 eLibrary © by author Opportunistic Infection Prophylaxis in HIV- associated malignancy (BHIVA 2014)
Co-trimoxazole Fluconazole Azithromycin Aciclovir ESCMID eLibrary © by author Conclusion What causes AIDS defining cancers?
Oncogenic virus related cancers
HHV8: KS, PEL & Castleman’s EBV: NHL, PCL & HD HPV: Anal & Cervical cancer ESCMID eLibrary © by author Conclusions Does cART effect AIDS cancers?
Incidence Respond to cART KS Falling Yes NHL Falling No Cervical No No (but CIN yes) cancer change ESCMID eLibrary © by author Conclusions: non-AIDS cancers Some associated with viral infections Anal cancer (HPV) Hodgkin lymphoma (EBV) Hepatoma (HBV, HCV)
Some not associated with known viruses Seminoma Non-small cell lung cancer ESCMIDMelanoma eLibrary © by author Conclusions: non-AIDS cancers
Risk not related to CD4 count
Not declining since cART
Do not respond to cART alone ESCMID eLibrary © by author