HIV and Malignancies S. De Wit St Pierre Hospital Brussels.

HIV and Malignancies

S. De WitSt Pierre HospitalBrussels

HIV and cancerHIV and cancer

• AIDS-defining malignancies:– Kaposi’s sarcoma– Non Hodgkin lymphoma 1985– Cervical cancer 1993

• Non AIDS-defining malignancies (NADM) is increasing

• Linked with virus HPVHPV (Anal), HBVHBV and HCVHCV (Liver), EBVEBV (HL)• Linked with previous immunodeficiency

HPVHPVEBVEBVHHV8HHV8

Background

• Before introduction of HAART, ADCs common, including Kaposi’s sarcoma, NHL, and invasive cervical carcinoma

• Rate of ADCs significantly increased from early to late pre-HAART era and then significantly decreased following introduction of HAART

• Rates of nADCs stable during pre-HAART eras and then significantly increased following introduction of HAART

Crum-Cianflone N, et al. AIDS. 2009;23:41-50.

SIR = Standardised Incidence RatioSIR = Standardised Incidence RatioNb cases of cancer in the HIV population

Expected nb of cases in the general population, calculated with local cancer registry incidence

Cancer Incidence in AIDS Patients

• Study of cancer risk in AIDS patients from 1980-2006 (N=372,364)

• Predominantly male (79%), non-hispanic black (42%), MSM (42%)

• Median age of 36 years at the onset of AIDS

Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 27.

Cancer type No. cases SIR 95% CI

AIDS-defining cancers

Kaposi sarcoma 3136 5321 5137 - 5511

Non-Hodgkin lymphoma

3345 32 31 - 33

Cervical cancer 101 5.6 5.5 - 6.8

Non-AIDS-defining cancers

Anal cancer 219 27 24 - 31

Liver cancer 86 3.7 3.0 - 4.6

Lung cancer 531 3.0 2.8 - 3.3

Hodgkin lymphoma 184 9.1 7.7 - 11

All non-AIDS related cancers

2155 1.7 1.5 - 1.8

SIR=Standardized Incidence Ratios

Cancer Mortality in AIDS Patients

Population attributable risk among people with AIDS in the US

Increased rates of nADCs. Why ?

• Increasing survival of patients with HIV might be associated with an increase of traditional cancer

• Aging of the HIV population• Life style• Long-term toxicity of ART ?

HIV associated cancers

Possible explanations: – Confounding by shared lifestyle cancer risk

factors – A direct effect of HIV, likely through an

effect of immune deficiency• Importance:

– If immune deficiency is responsible, then reversing immune deficiency might decrease cancer risk

Pathogenesis of NADC• Some are virally-induced cancers, but not all• HIV-tat may transactivate cellular genes or proto-

oncogenes, inhibit tumor suppressor genes• Microsatellite alterations (MA) due to genetic

instability in HIV (e.g 6 fold higher number of MA in HIV lung CA over non-HIV)1

• Increase susceptibility to effects of carcinogens (tobacco)

• Population differences based on genetics and exposure to carcinogens

• Decreased immune surveillance11Wistuba, AIDS 1999;13:415-26Wistuba, AIDS 1999;13:415-26

HIV & Cancers Role of immune deficiency ?

Cancer rate should also be increased in other immunosuppressive disorders

Infection-related cancers

EBV related cancers

Hodgkin lymphoma

HHV-8 related cancer Kaposi sarcoma

HBV/HCV related cancer Liver

HIV / AIDS Transplant

HIV / AIDS*

Transplant

HIV / AIDS*

Transplant

0.00 0.65

HIV / AIDS

Transplant

Cohort Meta-analysis SIR (95% CI) Heterogeneity

p-value Number

of studies

Stomach Transplant 0.85 HIV / AIDS

802 21

11.03 (8.43 - 14.44) 3.89 (2.42 - 6.26)

76.67 (39.37 - 149.29)

8.07 (6.40 - 10.17)

3640 (3326 - 3976)

208.0 (113.7 - 349.0)

5.22 (3.32 - 8.20)

2.13 (1.16 - 3.91)

2.04 (1.49 - 2.79) 1.90 (1.53 - 2.36)

3 7 0.49

1 10 100 1000

Helicobacter pylori related cancer

Observed number of cases

Figure 2: Standardised incidence ratios for cancers related to infection with Epstein-Barr virus, human herpesvirus 8, hepatitis B and C virus, and Helicobacter pylori in people with HIV/AIDS and in transplant recipients EBV=Epstein-Barr virus. HBV=hepatitis B virus. HCV=hepatitis C virus. HHV8=human herpesvirus8. *For AIDS-defining cancers, data from cohorts defined by an AIDS diagnosis included only those individuals who did not have that type of cancer at the time of AIDS.

Grulich et al. Lancet, 2007, 370, 59–

HPV related cancers Cervix uteri

Vulva and vagina

Oral cavity and Pharynx †

Possibly HPV related cancers Non-melanoma Skin ‡

Oesophagus

Larynx

HIV / AIDS* Transplant

HIV / AIDS Transplant HIV / AIDS Transplant HIV / AIDS Transplant HIV / AIDS Transplant

HIV / AIDS Transplant HIV / AIDS Transplant HIV / AIDS Transplant HIV / AIDS Transplant HIV / AIDS Transplant

2 2 3 1 6 2 4 3

4 3 2 5 4 3 5 3 2 2

0.00 0.67

0.55 0.85 0.52 -

0.03 0.04 0.07 0.37

0.00 0.00 0.45 0.00 0.53 0.28 0.55 0.88 0.92 0.35

104 22

21 6 303 18 238 49

121 448

30 506

48 28 142 20

5.82 (2.98 – 11.3) 2.13 (1.37 – 3.30)

6.45 (4.07 – 10.2) 22.76 (15.79 – 32.70)

4.42 (2.77 – 7.07) 15.79 (5.79 – 34.37)

28.75 (21.60 – 38.27) 4.85 (1.36 – 17.29)

2.32 (1.65 – 3.25)

3.23 (2.40 – 4.35)

4.11 (1.08 – 16.62) 28.62 (9.39 – 87.20)

2.80 (1.91 – 4.11) 30.00 (16.27 – 55.30)

1.62 (1.20 – 2.19)

3.05 (1.87 – 4.98)

2.72 (2.29 – 3.22) 1.99 (1.23 – 3.23)

1.98 (1.03 – 3.81) 6.94 (3.49 – 13.81)

.1 1 10 100 1000

p-value Number

of studies Observed number

of cases

Figure 3: Standardised incidence ratios for cancers related to, or possibly related to, human papillomavirus infection, in people with HIV/AIDS and in transplant recipients HPV=human papillomavirus. *For the AIDS-defining cancer (cervical cancer), data from cohorts defined by an AIDS diagnosis included only those individuals who did not have cervical cancer at the time of AIDS. †Excluding lip and nasopharynx. ‡Any measure of non-melanoma skin.

Common epithelial cancers

Trachea, bronchus, and lung

HIV / AIDS Transplant

1.63 (0.95 – 2.80) 1.55 (0.99 – 2.43)

2.72 (1.91 – 3.87) 2.18 (1.85 – 2.57)

Breast HIV / AIDS Transplant

1.03 (0.89 – 1.20) 1.15 (0.98 – 1.36)

0.60 0.66

Prostate HIV / AIDS Transplant

0.70 (0.55 – 0.89) 0.97 (0.78 – 1.19)

0.22 0.82

Colon and rectum HIV / AIDS Transplant

1016 234

194 156

202 98

224 185

0.92 (0.78 – 1.08) 1.69 (1.34 – 2.13)

0.34 0.11

0.34 0.61

0.00 0.25

.1 1 10 100 1000

p-value Number

of studies Observed number

of cases

Figure 4: Standardised incidence ratios for common epithelial cancers in people with HIV/AIDS and in transplant recipients

Cancers in HIV and transplant patients

• The range of cancers occurring at increased rates is strikingly similar in the two groups

• Mostly those known or suspected to be caused by infective agents

• Impact of immunodeficiency on these cancers

Clifford and Franceschi, Future Oncology 2009

CD4 and risk of liver cancer

Current CD4 count and death from cancer

D:A:D study group AIDS 2008, 22:2143–

Characteristics of cancer immune control

• CD4 cell count• CTL function• NK• Immune memory Central/effector memory• Level of immune activation:

– PD-1, IL-10, Treg

• Immune system on pre-cancerous lesions

Kaposi sarcoma 3136 5321 5137 - 5511

3345 32 31 - 33

Anal cancer 219 27 24 - 31

Liver cancer 86 3.7 3.0 - 4.6

Lung cancer 531 3.0 2.8 - 3.3

2155 1.7 1.5 - 1.8

Anogenital Cancers

• Invasive cervical carcinoma– Considered an AIDS-defining condition

• Anal cancer1

– Not AIDS defining but very common

• HPV involvement1-2

– Both derive from premalignant dysplastic lesions due to HPV– Most oncogenic strains: 16, 18, 31, 33, 35, 45– Repeated infections and infection with multiple HPV strains increase

the risk of developing neoplasia

1Phelps RM, et al. Int J Cancer. 2001;94:753-757.2Martin F, et al. Sex Transm Infect. 2001;77:327-331.

HPV-induced cancerHPV-induced cancer

• Cervix• Vulva• Vagina• Anal• Oro-pharyngal

• Penis

16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 69, 82

Schiffman, M. et al. N Engl J Med 2005;353:2101-2104

The Natural History of HPV Infection and Cervical Cancer

HIV- HIV+HIV+

Persistent HPVPersistent HPV 5-10% 20-40%20-40%

Cervical cancer Cervical cancer x 3-11x 3-11

Vulva & vagina cancer Vulva & vagina cancer x 4-10x 4-10

Infection with oncogenic HPV Infection with oncogenic HPV in HIV womenin HIV women

• Prevalence is higher :20-40% (vs.5-10%)

• Multiple genotypes: 40 % (vs. 12% )

• New infection? Reactivation of latent infection

• Linked with younger age, lower CD4 and higher HIV VL

Paleksky. J Natl Cancer Inst 1999

Strickler. Journal of the National Cancer 2005

D Konopnicki, Y Manigart, C Gilles, de Marchin J*, M Delforge, F Feoli*, P Barlow, S De Wit and N Clumeck. ECCMID 2011

Saint-Pierre CohortN=592

Prevalence of HR-HPV infection according to both age and CD4 cell strata (count/µL). (p=0.03, logistic regression)

EACS guidelines 2011. Available at http://www.europeanaidsclinicalsociety.org/guidelinespdf/EACS-EuroGuidelines_FullVersion.pdf . Accessed March 2011.

Problem Patients Procedure Evidence of benefits

Screening interval Additional Comments

Breast cancer

Women 50–70 yrs Mammography ↓breast cancer

mortality 1–3 years

Cervical cancer

Sexually active women

Papanicolau test,HPV DNA test

↓cervical cancer mortality 1–3 years

Target age group should include at least the age range 30 to 59 years. Longer screening interval if prior screening tests repeatedly negative

Colorectal cancer

Persons 50–75 yrs

Fecal Occult Blood test

↓colorectal cancer mortality 1–3 years Benefit is marginal

Cancer screening – EACSCancer screening – EACS

Screening in developing countriesScreening in developing countries• Screen-and-treat approach• Randomised , n=6555 with 956 HIV-positive women in South Africa,

35-65 years first screen. Excluded macroscopic lesions (6%)

• 3 arm– HPV test and cryotherapy– Visual inspection+ acetowhite detection and cryotherapy– Control : delayed at 6 months

• Women had colposcopy and biopsy at Month 6 (all), 12, 24 and 36 (subset)

HIV pos HIV neg ≥CIN2 at M36 15% 5% p=.0006Screen HPV RR M36 0.2 (0.06-0.07) 0.3 (0.02-.005) ps for

bothScreen VIA 0.51 (0.29-0.89) p=ns

Kuhn and al. AIDS 2010

Anal CancerAnal CancerInvasive cancerSIR 6-8 (in USA, St-Pierre Cohort)

PikettyAIDS 2008132 cases of invasive anal cancer among 86322 HIV-patientsMedian survival 5 years

RecentRecent PrePre EarlyEarly

Median CD4Median CD4 188 188 227227 288288Death due to ACDeath due to AC 50% 50% 40%40% 68.8%68.8%

http://clinicaloptions.com/hiv

Anal Cancer Incidence

• Incidence and risk of invasive anal cancer – Higher in HIV-infected vs age- and gender-matched general population (P

< .001)

• 60/100,000 PYs (95% CI, 40-89) vs 0.52/100,000 PYs (95% CI, 0.27-0.78)

– Nonsignificant difference in pre-HAART and post-HAART era for HIV-positive individuals (P > .05)

• 35/100,000 PYs (95% CI, 15-72) vs 92/100,000 PYs (95% CI, 52-149)

– Higher relative risk of anal cancer vs general population in post-HAART era

• Pre-HAART era, 67

• Post-HAART era, 176

Bower M, et al. J Acquir Immune Defic Syndr. 2004;37:1563-1565.

Anal Cytology Screening for AIN in HIV-positives

Screening Pap

Normal ASCUS

LSIL HSIL

Repeat in 12 months

Anoscopy with biopsy

Treat or follow Treat

No lesion seen

Chin-Hong PV et al. J Infect Dis. 2004;90:2070-2076.

LSIL HSIL

In summaryIn summary

• HPV-induced cancers are not reduced after cART introduction

• Screening should be improved for cervical cancer and for anal cancer

• Preventive vaccination against HPV should be more extensively studied and applied in HIV patients

Kaposi sarcoma 3136 5321 5137 - 5511

3345 32 31 - 33

Anal cancer 219 27 24 - 31

Liver cancer 86 3.7 3.0 - 4.6

Lung cancer 531 3.0 2.8 - 3.3

2155 1.7 1.5 - 1.8

Hodgkin’s Disease• Association with HIV-infection

– Hodgkin’s disease: RR: 5 to 30– Non-Hodgkin’s disease: RR: 24 to 165

• Patients with HIV present with:– B symptoms (70% to 96%), worse histology, higher-

stage tumor (74% to 92% are III or IV), bone marrow involvement (40% to 50%), pancytopenia

• Good response to MOPP/ABV– Complete response: 74.5%– 2-year disease-free survival: 62% – Early better results with Stanford V and BEACOPP

Gerard L, et al. AIDS. 2003;17:81-87.

Clifford and Franceschi, 2009

Risk of Hodgkin lymphoma by CD4 count

Kaposi sarcoma 3136 5321 5137 - 5511

3345 32 31 - 33

Anal cancer 219 27 24 - 31

Liver cancer 86 3.7 3.0 - 4.6

Lung cancer 531 3.0 2.8 - 3.3

2155 1.7 1.5 - 1.8

LUNG CANCER

SIR*Post-HAART

SIR*Pre-HAART

Studyn HIV Author

Reviewed in Lavolé, Lung Cancer 2005. *SIR is defined by the number of LC observed in the HIV-population/number of LC expected in the general population matched for age

Excess of risk of lung cancer in HIVExcess of risk of lung cancer in HIV

• Pre-HAART epidemiological studies

Savès, CID 2003

HIVNon HIV

% of smokers

– risk factors for cardiovascular disease

– age 35 to 44 years old– HIV patients, n=274 (APROCO cohort)– non HIV-persons, n=1038

(WHO-MONICA project)

• Bias due to difference of smoking habits in HIV ?

Parker, Chest 1998

SIR = 6.5

100 % of smokersunknown % of smokers

LC observed in HIVLC expected in HIV

• Bias due to difference of smoking habits in HIVexpected number of LC in the general population if 100 % of the

persons were smokers

• Bias due to difference of smoking habits in HIVexpected number of LC in the general population if 100 % of the

persons were smokers

SIR = 2.5

Cadranel, Respiration 1999; Bower, AIDS 2004

• Hypothesies for causal factors…– increased frequency of smoking in HIV population,

but intensity and duration not different– HIV status seems probable, but the mechanisms

remain unknown :• degree of immune deficiency• duration of immune deficiency• oncogenic role of HIV per se• other oncogenic virus• role of HAART

3p LOH, microsatellite alterations 9p21 LOH telomerase upregulation, MYC over expression 8p21-23 LOH neoangiogenesis, loss of FHIT, P53 mutations, aneuploidy, methylation 5q21 APC-MCC LOH, K-ras 12 mutation

Wistuba, JAMA 1997

Excess of risk, which mechanisms

Smoking

Increase of genomic instability ?

+ HIV + ID + HAART…

Lung Cancer

• Most frequent NADC in HAART era• Incidence 2-4 fold higher than general population

– SIRS between 2 and 3 and stable over time• Diagnosed at younger age with advanced disease

and primarily in smokers• Adenocarcinoma is most frequent sub-type• No clear screening strategy• No argument to treat differently than non-HIV

infected patients

Kaposi sarcoma 3136 5321 5137 - 5511

3345 32 31 - 33

Anal cancer 219 27 24 - 31

Liver cancer 86 3.7 3.0 - 4.6

Lung cancer 531 3.0 2.8 - 3.3

2155 1.7 1.5 - 1.8

Hepatocellular Carcinoma

• Linked to coinfection by hepatitis B and C viruses

• No clear difference between HAART users and non-users

• Estimated to be 7 times more frequent than in general population

• Optimal treatment similar to general population

Breast cancerBreast cancer

• No higher incidence in HIV-positive women

• There might even be a lower incidencelower incidence:– Significant decrease was recorded in Tanzania

following HIV epidemics. Amir. J Natl Med Assoc 2000

– Significant decrease in relative risk (observed cases/expected cases based incidence in general population ). Frisch. JAMA 2001

Why breast cancer could be less Why breast cancer could be less frequent in HIV women?frequent in HIV women?

• Reduced incidence is also found in other immunosuppressed patients

Steward. Lancet 1995

• Suggesting that physiological immune response is a facilitating factor in breast carcinogenesis

• Hormone production is reduced in HIV: oestradiol or testosterone

• Body composition change with HAART (waist gain)…and the USA obesity epidemics

• CXCR4-tropic HIV is protective against breast cancer because – In vitro: this receptor is highly expressed by tumor

cells and CXCR4 HIV induces tumor cells apoptosisEndo M. Curr HIV Res 2008

– In vivo : decreased incidence of breast cancer when compared to CCR5 HIV-infected patients

Hessol N . PloS ONE Dec 2010. vol 5;12:e14349.

• Ritonavir has been studied in preclinical trials for its activity against breast cancer growth

EACS guidelines 2011. Available at http://www.europeanaidsclinicalsociety.org/guidelinespdf/EACS-EuroGuidelines_FullVersion.pdf . Accessed March 2011.

Problem Patients Procedure Evidence of benefits

Screening interval Additional Comments

Breast cancer

Women 50–70 yrs Mammography ↓breast cancer

mortality 1–3 years

Cervical cancer

Sexually active women

Papanicolau test,HPV DNA test

↓cervical cancer mortality 1–3 years

Target age group should include at least the age range 30 to 59 years. Longer screening interval if prior screening tests repeatedly negative

Colorectal cancer

Persons 50–75 yrs

Fecal Occult Blood test

↓colorectal cancer mortality 1–3 years Benefit is marginal

Cancer screening – EACSCancer screening – EACS

Other Malignancies

• Non-melanomatous skin cancer• Conjunctival cancer• Sarcoma• Melanoma• Germ cell tumors• Other hematopoietic neoplasms including

myeloma and leukemia• Many present with advanced disease at diagnosis

HAART and chemotherapy• Many patients will receive HAART and

chemotherapy concurrently with high likelihood of drug interactions

• Protease inhibitors and non-nucleoside reverse transcriptase inhibitors are substrates and potent inhibitors or inducers of cytochrome P450 system (CYP)– Many anti-neoplastic drugs also metabolized by CYP

system leading to either drug accumulation and possible toxicity or decreased efficacy

• Paclitaxel and docetaxel• Vinca alkaloids

Summary

• Since introduction of HAART, NHL and KS incidence has decreased

• Incidence of other cancers has increased related to other risk factors – immunosuppression, viral coinfections, smoking

• Prevention via risk factor control and screening• Optimization of antiretroviral treatment• Treatment strategies similar for non-HIV infected

individuals

HIV and Malignancies S. De Wit St Pierre Hospital Brussels.

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