HIV and

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

Malignancy

Kaposi’s KSHV

Non-Hodgkin’s (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 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 ? 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

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-

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 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 : (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 Lung cancer Colorectal cancer

Women Breast cancer Breast cancer Melanoma Lung cancer Colorectal cancer ESCMID eLibrary ©Bower Mby and Waxman J.author Lecture notes: , 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 and 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 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 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 virus Choo et al. Science 244, 359-362 1994 Kaposi’s sarcoma Herpesvirus Chang et al. Science 265, 1865-1869 2008 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 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 (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 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