Jean Anderson, MD Catherine Sewell, MD, MPH

Jean Anderson, MD Catherine Sewell, MD, MPH

To review diagnosis and management of HPV disease in the setting of HIV infection and address controversies

HIV-infected women have: higher prevalence and incidence of HPV longer persistence of HPV higher HPV viral loads higher likelihood of multiple HPV subtypes greater prevalence of oncogenic subtypes HPV prevalence, persistence and viral load increase with decreasing CD4 count and increasing HIV-RNA levels Oncogenic subtypes may be more common with lower CD4 counts and/or higher viral loads ACOG Practice Bulletin #117 Gynecologic Care for Women with Human Immunodeficiency Virus. December 2010

Abnormal cervical cytology more common among HIV+ women, assoc with HPV Frequency and severity of abnormal pap smears and documented dysplasia increase with declining CD4 counts and higher HIV-RNA levels Progression/regression of abnormal paps associated with CD4 and HIV-RNA level More extensive cervical involvement and more likely to involve other sites in lower genital tract ACOG Practice Bulletin #117 Gynecologic Care for Women with Human Immunodeficiency Virus. December 2010

In 1993 invasive cervical cancer (ICC) became an AIDS-defining illness (ADI) Women with HIV and ICC younger than HIVnegative women with cervical cancer HIV-positive women with ICC have poorer responses to therapy, higher recurrence and death rates, and shorter intervals to recurrence or death Incidence of ICC has not changed since ART introduced 6

After initial HIV diagnosis, perform two Pap smears 6 months apart If both initial Paps are within normal limits, repeat on annual basis Perform colposcopy with directed biopsies with Pap smear showing ASCUS, SIL or squamous cell carcinoma Data insufficient to support use of HPV DNA testing for triage of ASCUS in HIV+ women (MMWR 2009;58: No. RR-4) Perform colposcopy with endocervical sampling for AGC/AIS; endometrial sampling should be done in women >35 yr. ASCCP guidelines should be followed when CIN is identified and for further evaluation of AGC/AIS ACOG Practice Bulletin #117 Gynecologic Care for Women with Human Immunodeficiency Virus. December 2010

36 yo P3013 HIV+ diagnosed 1991 Long-term non-progressor Long hx substance abuse, nonadherence with care HSIL pap 2004, no follow-up Pap 10/2006 HSIL Lost to follow-up until 3/2009: Started on HAART for CD4 nadir 227, VL 17, 436 Colposcopy: satisfactory, acetowhite change into canal at 11:00 Biopsies: 11:00 CIN3, ECC: low grade, possibly high grade dysplasia

Goal: rule out invasive disease, destroy preinvasive disease Excision or ablation Cryotherapy *LLETZ /LEEP Laser ablation *Cervical conization Excisional procedures preferred because pathology is obtained Hysterectomy is NOT a primary treatment for HSIL Increase in HIV shedding in genital tract 2-4 wks after treatment emphasize abstinence while healing ACOG Practice Bulletin #117 Gynecologic Care for Women with Human Immunodeficiency Virus. December 2010

Less-advanced immunosuppression and early stages of intraepithelial neoplasia (IN) may best respond to HAART due to restoration of HPVspecific immune responses Poorer response to HAART with IN 2-3 Inability to restore HPV specific immunity or Accumulation of genetic mutations so that restoration of HPV immunity insufficient to cause lesion regression

Data mixed re: effect of ARV on HPV prevalence/persistence, incidence/regression/progression of dysplasia Some studies show increased regression and decreased progression of cervical cytologic abnormalities/dysplasia, others show enhanced HPV clearance but no regression of cytologic changes, others show no change in either Different study design, screening/diagnostic protocols, virologic/immunologic parameters, duration and type of ART, length of follow-up, etc Possible restoration of immune competence and longevity means increased chance for cumulative exposure to HPV infections and accumulation of somatic mutations and epigenetic changes that contribute to carcinogenesis Recommendations for evaluation and follow-up are unchanged in women on HAART AIDS 2002:16:1799; AIDS 2001;15:2157; Obstet Gynecol 2009;113(1):26; J Acquir Immune Defic Syndr 2009;51(3):274, J Infect Dis 2001;184:547, J Transl Med 2009;7:108

7/2009: cold knife cone biopsy, R. vaginal fornix biopsy, fourchette biopsy, anal pap CIN3 with positive endocervical/deep margins, ECC CIN3 Vaginal biopsy: benign, fourchette: genital wart Anal pap: ASCUS Repeat cold knife cone biopsy 10/2009 Cone pathology negative ECC CIN3 Relapsed drug use, lost to follow-up

Increased recurrence rates after standard treatment; increased recurrence with lower CD4 counts Recurrent cervical abnormalities after excisional treatment associated with detectable HIV-RNA and higher mean HIV-RNA levels (Keller,2000) Positive surgical margins more likely with cervical conization in HIV+ vs HIV- women (48% vs 33%) (Boardman, 1999)

3/2010: pap HSIL, CD4 off meds 594, VL 17,756, restarted HAART 4/2010 radical hysterectomy: pathology showed extensive CIN3 and extension to endocervical glands Recommended paps q 6 months 9/2011 pap negative, lost to follow-up (incarcerated)

Cytotoxic agents and keratolytic agents: Imiquimod (Aldara ) - topical immune response cream applied to the affected area 20% podophyllin - anti-mitotic solution applied to the affected area and later washed off 0.5% podofilox solution, applied to the affected area but not to be washed off A 5% 5-fluorouracil (5-FU) cream Trichloroacetic acid (TCA) liquid nitrogen / cryotherapy Cytodestructive techniques CO2 laser vaporization Electroexcision / fulguration Cryotherapy CUSA (Cavitron UltraSonic Aspirator)

Recurrence rate THERAPY HIV- HIV+ Cryotherapy 25-39% 53% Elect.dessication 25% 38% LEEP 51% Unknown Excision 19-22% 33% TCA 36% Unknown Podophyllin 22-65% 51.5% Podofilox 16-34% 7% Imiquimod 22% 17-29%

WIHS: 470 HIV+, 185 HIV- HIV+ more likely to have Abn l anal cytology /histology (31% vs 9%,p<.001) Abn l cervical cytology/histology (34% vs 19%, p=.003) anal and cervical HPV (p<.001) No diff in hx anal sex HIV+ vs HIV- Among HIV+ women incidence of invasive anal cancer is 7-28X greater than in general population (J Natl Ca Inst 2000, Br J Ca 2003) Hessol et al. AIDS 2009;23:59; das Gracas M, et al Int J Colorectal Dis 2012;27:271-276.

Gimenez et al at the Tropical Medicine Foundation of Amazonas 2011 128 HIV (+) women underwent anal pap and HRA with biopsy Prevalence of anal HPV infection was 79% and anal SIL was 39.1% HRA had sensitivity of 90%, specificity of 19%, PPV of 41.7%, and NPV of 75% Anal receptive intercourse and anal HPV infection were significantly associated with anal SIL (p=0.049 and p=0.006) Gimenez F et al Arq Gastroenterol 2011;48(2):136-145

Machalek et al meta-analysis of 53 studies of prevalence, incidence of anal HPV, AIN, and anal cancer in MSM Among HIV (+) men: Anal HPV and anal cancer precursors are very common (35.4% and 29.1% prevalence, incidence 13% and 8.5-15.4%) Rates of progression seem to be substantially lower than for cervical pre-cancerous lesions (anal cancer incidence 45.9/100,000 men) Need large good quality prospective studies to inform development of anal cancer screening guidelines for MSM Machalek, DA, et al. Lancet 2012;DOI:10.1016/S1470-2045(12)70080-3.

Benefits of screening with anal cytology for women remain unclear No current recommendation for routine screening need evidence that screening and treatment of lesions reduces risk of progression to anal ca No current recommendations for HPV testing of anal specimens Providers should inquire about anal sx (itching, bleeding, pain) and perform visual inspection and digital exam yearly Consider anal cytology in: any patient with history of anogenital condylomas abnormal cervical cytology Patients with abnormal anal Pap test should be referred for high-resolution anoscopy and possible biopsy Palefsy. Top HIV Med 2007;15(4)

Condom use-assoc with 72% reduction HPV acquisition in college age women (NEJM 2006); may reduce risk of CIN, warts, ICC (Ca Epidemiol Biomarkers Prev 2006, Sex Transm Dis 2002) Male circumcision MC clinical trial in S Africa: HRHPV prev 14.8% in MC group vs 22.3% in controls (RR.66) (JID 2009) HPV vaccine: Quadrivalent (6,11,16,18) and bivalent (16,18)-100% protection against incident infection with HPV16, 18 (Lancet Oncol 2005, Vaccine 2006)

Models estimate that reduction in incidence and mortality CxCa greatest in low/middle income countries with no or limited screening May be cost-effective if cost <$10-25/vaccinated girl WHO: recommends including routine HPV vaccination in national immunization programs, providing prevention CxCa public health priority, programmatically feasible, cost-effective, sustainable financing. CDC recommends HPV vaccination of children and adolescents in HIV infected and uninfected populations

Issues to be clarified: Safety and immune response shown in children only so far 120 HIV (+) children aged 7-11: >99.5% developed antibodies against HPV, but GMTs for types 6, 18 lower for HIV (+) than for age-matched historic controls Sufficient numbers of HIV+ individuals who are not already infected with HPV to determine vaccine efficacy Ability to mount protective antibody titers against HPV efficacy in women and girls with HIV has not yet been established Ability to maintain protection and for how long Palefsy. Top HIV Med 2007;15(4), ACOG Practice Bulletin #117 Gynecologic Care for Women with Human Immunodeficiency Virus. December 2010

WHO: concerns about safety/efficacy in HIV+ girls should not delay large scale immunization and HIV testing should not be prerequisite (April 2009)

HPV and cervical dysplasia more prevalent with higher likelihood of persistence and recurrence, correlating with immune status and perhaps treatment status HPV disease multifocal Screen entire lower genital tract and consider anal pap in those at risk Treat pre-invasive disease

Jean Anderson, MD Jean Keller, PA-C Adriana Andrade, MD, MPH