Catching up on HPV-related cancers: diagnostic advances and treatment controversies

Nittaya Phanuphak, MD, PhDThai Red Cross AIDS Research Centre

Bangkok, Thailand

Outline

• HPV – HIV – Cancers

• Screening programs to prevent cervical cancer and anal cancer

• Facts and challenges when making decision to screen/treat anal pre-cancerous lesions

HPV – HIV – Cancers• HAART prolongs survival of PLHIV but may have incomplete

immune recovery

• Lack of decline or increased incidence of HPV-related cancers among PLHIV in the HAART era

Palefsky JM 2011

Cervical cancer in HIV+ women

1980-1989 1990-1995 1996-20040

100

200

300

400

500

177.3

448.9

70.989 90.4

In situ Invasive

Chaturvedi AK, et al. J Natl Cancer Inst 2009;101:1120-30.

SIR 8.9 for in situ cancer, 5.6 for invasive cancerIn

cide

nce

per 1

00,0

00 P

Y

1980-1989 1990-1995 1996-20040

102030405060708090

100

1.718.3

29.510.5

20.7

42.3

InvasiveIn situ

Anal cancer in HIV+ men and women

1980-1989 1990-1995 1996-20040

102030405060708090

100

0 1.7 5.20

5.2 11.2

Inci

denc

e pe

r 100

,000

PY

Chaturvedi AK, et al. J Natl Cancer Inst 2009;101:1120-30.

SIR In situ InvasiveMales 68.6 34.6 - MSM 89.7 51.8Women 33.0 14.5

MEN WOMEN

Oropharyngeal cancer in HIV+ men and women

1980-1989 1990-1995 1996-20040

10

20

30

40

50

0 3.96.5

Invasive

Chaturvedi AK, et al. J Natl Cancer Inst 2009;101:1120-30.

SIR 1.6

Inci

denc

e pe

r 100

,000

PY

HPV infection and dysplastic transformation

CancerNormal

Low-grade squamous

intraepithelial lesion (LSIL)

High-grade squamous

intraepithelial lesion (HSIL)

Modified from Palefsky JM 2011

Screening program and prevention of cervical cancer

• Rates of cervical cancer have declined in settings where screening programs have been implemented successfully– No RCT performed prior to widespread screening

program– Observational studies confirmed risk of invasive

cancer in women with high-grade cervical dysplasia• Screening programs remain difficult to

implement in low and middle-income settings

McCredie MR, et al. Lancet Oncol 2008; 9: 425–34.McIndoe WA, et al. Obstet Gynecol 1984;64:451-8.

Screening program and prevention of anal cancer

YES• More clinics now offer

screening for anal HSIL among patients at “high risk” for anal cancer, as a strategy to prevent anal cancer, based on the etiological and pathological similarities to cervical cancer

NO• More research is needed

to understand the natural history of anal HSIL and to prove the efficacy and acceptability of its treatment

Pria AD, et al. AIDS 2013; 27: 1185-6.Grulich AE, et al. Sex Health 2012;9:628-31.

HPV in-fection

CIN0

20

40

60

80

100

35

1924

4

HPV infectionHPV in-fection

CIN0

20

40

60

80

10083

16

70

6

Any HPV typesHigh-risk HPV types

HPV infection

Cervical HPV and histologic HSIL among HIV+ women

• Progression of CIN 3 to cervical cancer = 1 in 80 per year

Prev

alen

ce (%

)

Histologic SIL

SUN (US) THAILAND

Histologic SIL

Kojic EM, et al. Sex Transm Dis 2011;38:253-9.Ramautarsing R, et al. 27th Int HPV Conf 2011, Berlin, P-32.33.

Chaturvedi AK, et al. J Natl Cancer Inst 2009;101:1120-30.McCredie MR, et al. Lancet Oncol 2008;9:425-34.

All histologic SIL

Histologic HSIL

Cervical cancer rate in HIV+ women = 90 / 100,000

HPV in-fection

AIN0

20

40

60

80

100

14 9

HPV infectionHPV in-fection

AIN0

20

40

60

80

100 90

16

85

9

Any HPV typesHigh-risk HPV types

HPV infection

Anal HPV and histologic HSIL among HIV+ women

• Anal SIL is as common as cervical SIL• More common in women with cervical, vulvar, vaginal

high-grade diseases

Prev

alen

ce (%

)

SUN (US) THAILAND

Histologic SIL

Hessol NA, et al. AIDS 2009;23:59-70.Chaithongwongwatthana S, et al. IGCS 2012.

Chaturvedi AK, et al. J Natl Cancer Inst 2009;101:1120-30.

All histologic SIL

Histologic HSIL

Anal cancer rate in HIV+ women = 11 / 100,000

0

20

40

60

80

10085

5958

37

1911

HIV-positive

Anal HPV and histologic HSIL among HIV+ and HIV- MSM

• Progression rate of anal HSIL to cancer (per year)– Theoretical: HIV+ MSM = 1 in 600, HIV- MSM = 1 in 4000– Australia (73% HIV+ MSM): 1 in 80

Prev

alen

ce (%

)

HIV-negative

THAILAND

Phanuphak N, et al. JAIDS 2013 (In press). Phanuphak N, et al. AIDS 2013 (In press). Hu Y, et al. JAIDS 2013 (In press). Tong WWY, et al. AIDS 2013 (In press).

Machalek DA, et al. Lancet Oncol. May 2012;13(5):487-500.

0

20

40

60

80

10082

5861

40

Any HPV typesHigh-risk HPV types

HIV-positive

CHINA

0

20

40

60

80

100 93

6474

3729

22

Any HPV typesHigh-risk HPV types

HIV-positive

Meta-analysis

HIV-negative HIV-negative

Anal cancer rate in HIV+ MSM = 78 / 100,000 and in HIV- MSM = 5 / 100,000

Prev

alen

ce (%

)

Anal HSIL screening

New York State Department of Health AIDS Institute: www.hivguidelines.org Oct 2007.Palefsky JM 2011.

• No standard screening guidelines• New York State Department of Health AIDS Institute• Screen at baseline and annually for HIV+: MSM, anogenital

warts, abnormal vulvar/cervical histology

Need for better biomarkers for screening

• Anal cytology limitation– Low sensitivity and poor correlation with histologic grading

• HRA limitation– Expensive and very limited number of trained

physicians/nurses

• Potential HGAIN biomarkers– p16 and other cell cycle markers: immunocytochemistry– E6/E7 mRNA: flow cytometry– E6 oncoproteins: rapid test– HPV DNA detection: screening test/genotyping assay

Panther LA, et al. Clin Infect Dis. 2004;38:1490-1492.

Biomarkers for anal HSIL

Phanuphak N, et al. (Submitted)

Best for detection of disease

at that visit

Best for prediction of disease

In the future

Treatment of anal HSIL• Various “in-office” treatment options are available

• Side effects are not uncommon but manageable, some concerns about long-term sexual functioning

• Treatment causes regression of lesions, although no prove that it will prevent anal cancer

• Recurrence rate is substantial but usually is minimal

• Better treatment modalities are needed

Richel O, et al. Lancet Oncol 2012;14:346-53.Fox PA. Sex Health 2012;9:628-31.

Treatment of anal cancer• Combination chemoradiation as the first-line therapy

• In very selected cases, local excision may be used as primary treatment, often with chemoradiation

• Salvage abdominoperineal resection for persistent or recurrent anal cancers

Szmulowicz UM and Wu JS. Sex Health 2012;9:593-609.SEER 2011.

Stage 5-year survival (%)Localised (confined to 1ry site) 79.0Regional (spread to regional LN) 58.5Distant (metastasised) 29.6

Do I want to screen my patient?

YES• What do you want to

screen for?– Anal cancer: Digital

ano-rectal exam– Anal HSIL: Cytology+/-

HSIL biomarkers and high-resolution anoscopy

No• More research is

needed on– Natural history of

anal HSIL

Do I want to treat anal HSIL in my patient?

YES• Use treatment

modalities currently available

• More research is needed on– Better treatment of

anal HSIL

No• Frequent follow-up• More research is

needed on– Natural history of

anal HSIL– Anal cancer

biomarkers– Better treatment of

anal HSIL and its side effects

Summary• HAART not reducing HPV-related cancers – Some cancers increasing

• HIV+ men and women are more likely to have HSIL than HIV- men and women– High prevalence of anal HSIL in HIV+ MSM and

women• Several challenges are there when considering

screening programs for anal HSIL– Dependent on clinician’s interpretation of the data

and readiness of the local health systems

AcknowledgmentsThai Red Cross AIDS Research Centre • Nipat Teeratakulpisarn• Praphan Phanuphak• Tippawan Pankam• Jiranuwat Barisri• TRC Anonymous Clinic staff• Our clinic clients & study participants

Chulalongkorn University• Somboon Keelawat• Surang Triratanachat• Surasith Chaithongwongwatthana• Preecha Ruangvejvorachai• Sarunya Numto

UCSF• Joel Palefsky

TREAT Asia• Annette Sohn

The AIN Biomarker Study is funded by the US NIH, through a grant to amfAR for the International

Epidemiologic Databases to Evaluate AIDS (IeDEA); NIAID/NCI/NICHD, UO1AI069907.

HIV-NAT and SEARCH• Jintanat Ananworanich• Steve Kerr• Cecilia Shikuma• Reshmie Ramautarsing

Srinakharinwirot University• Piamkamon Vacharotayangkul