Slide 1 of 23

Say Yes to the Test!

Jeffrey L. Lennox, MD

Professor of Medicine Emory University School of Medicine Atlanta, GA

IAS –USA

A Brief History of the Cervical Pap Smear

• 1928 – Papanicolaou presents methods and case reports. Received press attention, but little interest from medical establishment.

• 1941 – Papanicolaou publishes additional data.

• 1955 – First large study completed.

• Late 50’s–60’s – Refinements, training of cytologists.

• 1984 –

82% reduction

in cervical cancer mortality compared to 1940’s.

From JL Lennox, MD, and KA Workowski, MD, at Atlanta, GA: April 10, 2013, IAS-USA.

In the

30 years after

the description of the Pap smear, but before its acceptance,

cervical cancer was the #1 cause of cancer mortality

in women

Why Did the Medical Establishment Reject Cervical Pap Smears?

• New test, no proof of efficacy and benefit • Insufficient training and expertise of pathologists • Additional costs to screen • Wide variability in results between labs • Bias against women, particularly with regards to STIs

Anal Pap Smear Among HIV-Infected Men: 27 years since first description

• 1986 – “Association Between Anorectal Dysplasia, HPV and HIV in Homosexual Men”* • Obtained rectal Paps from 61 men, 39 re examined 6-12 months later • 31% HIV+ • Findings: −24/61(39%) had dysplasia −Dysplasia associations – history of anal warts, frequent receptive anal sex, HIV+ −

Persistent dysplasia more common in HIV+

* Frazer IH,

Lancet

1986, 328(8508):657 –660

Incidence of Anal Cancer in HIV-Infected Persons During HAART Era 34,189 HIV-infected patients from 13 North American cohorts 131-159 per 100,000 person-years,

31-59% higher than the peak for cervical cancer

!

Silverberg MJ,

Clin Inf Dis

2012, 54(7):1023-34

Are all HIV-infected men equally at risk?

• Cross sectional study of 200 MSM and 123 MSW, all HIV-infected, who had anoscopy performed.

1 • Dysplasia present: 21% MSM, 7% MSW Characteristic CD4 <200 History rectal condyloma

Anal Dysplasia

OR (95%CI) 1.7 (0.8-4.4) 2.8 (1.4-5.8) p 0.235

0.004

Receptive anal intercourse 4.3 (2.2-8.4) <0.001

• Military cohort- median anal cancer age 42 years.

2 • Persons with HIV >15 years had 12x higher rate than those <5 years (p<0.01) 1. Abramowitz L,

AIDS

2007, 21(11): 1457-65. 2. Crum-Cianflone and Marconi, AIDS, Feb 2010

How Well does the Anal Pap do When Compared to Biopsy?

Chiao EY,

JAIDS

2006;43:223-233

Cost Effectiveness of Anal Cytology Screening in MSM

Population

HIV+ MSM HIV- MSM

Frequency

Annually Q 3 years

Cost per QALY Saved

$16,000 $7,800 Goldie SJ.

JAMA

1999, 281(19):1822-1829

Cost Effectiveness of Other Common Interventions

Intervention

Q2 yr cervical Pap age 30-39 PCP prophylaxis HTN screening men age 40 Treat diastolic BP 95-104, age 40 Statin for men age 40, TC >300 Colonoscopy for CA screening Cervical Pap, HPV vaccinated woman

Cost/yr life

$2,300 $16,000 $23,000 $32,000 $23,000 $90,000 $110,000 Anal Pap Goldie SJ.

JNCI

2004;96:604-615

Cost Effectiveness of HRA Only vs. Pap for Screening - Methods

• 401 HIV+ MSM had HRA, Pap, and HPV digene assay done at same visit.

• 98/401 (24%) had AIN 2/3 based on biopsy during HRA.

• For sensitivity and specificity the HRA biopsy was assumed to be gold standard .

Test

HRA Pap Ocogenic HPV

Sensitivity

84 100

Specificity

39 16

Cost/Test

$193 $90 $95 Lam JMC,

AIDS

2011, 25: 635-42

Cost Effectiveness of HRA Only vs. Pap - Results

Insert figure HPV+ : HRA Pap > ASCUS: HRA HRA Conclusion: Direct HRA is the most cost effective

Random Biopsy Increases HGSIL Diagnostic Rate of HRA

• 372 patients had HRA with directed and random biopsies done at same visit • 124 patients with HSIL, 11 (9%) diagnosed by random biopsy Silvera R, CROI 2013, #142

New York State Guidelines

Clinicians should obtain anal cytology at baseline and annually in the following HIV-infected populations:

* Men who have sex with men * Any patient with a history of anogenital condylomas * Women with abnormal cervical and/or vulvar histology

My Conclusions –

1. For those with HIV of >5 years duration, use direct HRA if available for MSM and other high risk people 2. Use Pap as second choice, followed by HRA 3. When performing HRA do 1-3 random biopsies

Slide 16 of 23

Anal Cancer Prevention 1

st

!

Kimberly A. Workowski, MD

Professor of Medicine Emory University School of Medicine Atlanta, GA From JL Lennox, MD, and KA Workowski, MD, at Atlanta, GA: April 10, 2013, IAS-USA.

IAS –USA

Slide 17 of 23

Natural History of HPV Infection

• HPV persistence is a prerequisite for abnormal anogenital cytology • Most infections self limited – Limited data on persistence in specific anatomic sites (HIV+) – Anal dysplasia +/- treatment not well defined • Incidence and clearance rates can differ among HPV types – HPV16 lower anal clearance rate (dePokomany 2009) From JL Lennox, MD, and KA Workowski, MD, at Atlanta, GA: April 10, 2013, IAS-USA.

Slide 18 of 23

HPV Vaccine Efficacy

Randomized Controlled Trials

Efficacy

Cervical precancer Bivalent and Quadrivalent F >92% Vaginal/Vulvar precancer

Anal precancer

Quadrivalent

Quadrivalent

F

M

100%

75%

Genital warts Quadrivalent F, M >89%

No evidence of efficacy against existing HPV infection or disease Paavonen J et al. Lancet 2009;374:301-14, Kjaer S et al. Cancer Prev Res 2009;2:868-78, Hildesheim A et al. JAMA 2007;298:743-53, Future I/II Study Group, BMJ 2010;341, The Furture II Study Group Lancet 2007;369:1861-8, Palefsky J et al. NEJM 2011;365:1576-85 Gardasil Package Insert, page 504 Table 12

From JL Lennox, MD, and KA Workowski, MD, at Atlanta, GA: April 10, 2013, IAS-USA.

Slide 19 of 23 HPV vaccine –preventable fractions of various anal disease categories among HIV+ MSM Sahasrabuddhe. J Infect Dis. 2013 Feb;207(3):392-401

.

From JL Lennox, MD, and KA Workowski, MD, at Atlanta, GA: April 10, 2013, IAS-USA.

Slide 20 of 23 Time to recurrence of high-grade anal neoplasia among vaccinated and unvaccinated oncogenic human papillomavirus –infected men who have sex with men with a history of high-grade anal neoplasia New York City, April 2007 – April 2011 (n = 105).

Figure 2. Swedish KA, Factor SH, Goldstone SE. Prevention of recurrent high-grade anal neoplasia with quadrivalent human papillomavirus vaccination of men who have sex with men: a nonconcurrent cohort study. Clin Infect Dis. 2012 Apr; 54(7):891-8. From JL Lennox, MD, and KA Workowski, MD, at Atlanta, GA: April 10, 2013, IAS-USA.

Slide 21 of 23 Predictors of progression from low-grade AIN (LGAIN) to high-grade AIN (HGAIN) Coutlée F.Sex Health. 2012 Dec;9(6):547-55.

From JL Lennox, MD, and KA Workowski, MD, at Atlanta, GA: April 10, 2013, IAS-USA.

Slide 22 of 23 Logistic Regression Analysis of Factors Associated with Prevalent Abnormal Anal Cytology among MSM in the SUN Study, 2004 –2006 Conley L. J Infect Dis. 2010 Nov 15;202(10):1567-76.

From JL Lennox, MD, and KA Workowski, MD, at Atlanta, GA: April 10, 2013, IAS-USA.

Slide 23 of 23

Screening for Anal Dysplasia and Cancer in MSM



CDC, HIVMA OI guidelines:

consider

anal Pap tests in MSM

– • • • •

Evidence is limited Natural history Reliability of screening methods Safety and response to treatments Programmatic support needed

–

Patients with abnormal results should be evaluated with high resolution anoscopy (HRA)



HPV DNA screening of rectum not recommended

From JL Lennox, MD, and KA Workowski, MD, at Atlanta, GA: April 10, 2013, IAS-USA.