HIV and Cervical Cancer Screening

Jean Anderson M.D. Director, Johns Hopkins HIV Womens Health Program Senior Technical Advisor, Jhpiego

Interrelationship of HIV and HPV

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

Meta-analysis of cervical HPV in HIV+ women with normal cytology: >55% in Africa, S. America; >30% in Asia, N. America, Europe 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
Ellerbrock 2000, Hawes 2003, Schuman 2003, Massad 2001, DeVuyst 2008, Denny 2008, Sahasrabuddhe 2007, Clifford 2006

HIV and Lower Genital Tract Neoplasia

Abnormal cervical cytology/histology more common among HIV+ women, assoc with HPV Up to 10x higher rates Frequency and severity of abnormal pap smears and documented dysplasia increase with declining CD4 counts and higher HIV-RNA levels HERS: prevalence SIL with CD4>500 equiv to HIV-; prevalence of SIL with CD4<100: LSIL 27%, HSIL 11% Progression/regression of abnormal paps associated with CD4 and HIV-RNA level and HPV More extensive cervical involvement and more likely to involve other sites in lower genital tract
Maiman 1998,1990; Massad 2008, 2001; Schuman 2003

Invasive Cervical Cancer in HIV Disease

1993 -invasive cervical cancer (ICC) becomes an AIDS defining illness (ADI) Women with HIV and ICC younger and less immunosuppressed vs HIV+ women with other ADI (Phelps
2001)

Women with HIV and ICC younger than HIV- women with cervical cancer (Lomalisa 2000) HPV subtypes in SCC (S. Africa, Kenya): 16 or 18 in 67%, multiple types 21% (vs 3% in HIV-) (DeVuyst, CROI 2011) Incidence of ICC not increased among HIV+ women with regular screening, recommended f/u (Massad 2004, 2009)

ARV Therapy and Cervical Dysplasia/HPV

Data mixed re: effect of ARV on HPV prevalence/persistence, incidence/regression/progression of dysplasia Recommendations for evaluation and followup are unchanged in women on HAART

Minkoff 2001, 2010; Heard 2002; Paramsothy 2009; Fife 2009; Lillo 2001

Palefsky. Curr Opin Oncol 2003

+++ ++ +/-

Visual Inspection with Acetic Acid (VIA): A Low Cost, Low Tech Alternative to Cytology
Pap smear often not available in low-resource settings: limited health infrastructure, lack of trained cytology technicians/pathologists, cost, need for recall with abnormal results VIA (standard HGCIN 2+): sensitivity: 79-82%; specificity:9192%; PPV: 9-10% (Sauvaget 2011); associated with 24% decrease cervical cancer incidence, 35% decrease cervical cancer mortality , compared to no screening (Sankaranarayanan 2007) VIA
Inexpensive Safe, feasible and acceptable in multiple studies

Allows treatment at same visit (Single Visit Approach or SVA)

A Multi-Country Program Using VIA for Cervical Cancer Screening: Jhpiego

Implemented in Cote dIvoire, Guyana, Tanzania in 2008-2012 National Service Delivery Guidelines and Protocols Standardized training package utilizing hands-on practicum and skills/knowledge level assessment Same visit counseling, screening and treatment for eligible VIA+ women (SVA) provided by trained nurses/midwives Transfer of learning and supportive supervision to ensure high quality of care Robust monitoring and all-level data use approach to support target coverage and quality control Community education to increase demand for screening

Variable
Service delivery period Number of project sites Primary population at screening clinic

Sub variable
Start end date Total HIV Care and Treatment sites (%) General population (% ) Urban (%)

Cote dIvoire
Oct 2009 Sep 2011 10 10 (100%) 0 (0%) 10 (100%) 0 (0%) 0 (0%) 1 (10%) 2 (20%) 5 (50%) 2 (20%) 46 22 (48%)

Guyana
Jan 2009 Sep 2011 16 5 (31%) 11 (69%) 6 (38%) 2 (13%) 8 (50%) 2 (13%) 6 (38%) 5 (31%) 3 (19%) 43 21 (49%)

Tanzania
April 2010 Sep 2011 10 10 (100%) 0 (0%) 2 (20%) 1 (10%) 7 (70%) 0 (0%) 2 (20%) 6 (60%) 2 (20%) 34 11 (32%)

Total
Jan 2009 Sep 2011 36 25 (69%) 11 (31%) 18 (50%) 3 (8%) 15 (42%) 3 (8%) 10 (28%) 17 (47%) 6 (17%) 123 54 (44%)

Facility location

Peri-urban (%) Rural (%) National Hospital (%)

Facility Type

Regional Hospital (%) District Hospital (%) Health Center (%)

Number of people trained Cadre of trained cervical cancer screening providers

Total Physician / Medical Doctors / Clinical Officers / Asst. Medical Officers (%) Medex (%) Nurse (%) Midwife (%)

0 (0%) 3 (7%) 21 (46%) 17(3 - 24) 33 (29 - 55)

6 (14%) 9 (21%) 7 (16%) 15 (0 - 33) 40 (25 - 55)

0 (0%) 23 (68%) 0 (0%) 15 (11 - 24) 42. (26 - 61)

6 (5%) 35 (28%) 28 (23%) 14 (0 - 33) 38 (25 - 61)

Average length of time providing screening Age of provider (years)

Monthly Average (Range) Average (Range)

Table X. Baseline facility and provider characteristics by country

Cervical Cancer VIA Screening and Treatment Outcomes for 3 Countries

New Women screened 5,160 Cote dIvoire 17,598 Guyana 5,142 Tanzania

Suspect cancer cases detected and referred 39 (0.8%) Cote dIvoire 87 (0.5%) Guyana 115 (2%) Tanzania

VIA Screen positive 404 (8%) Cote dIvoire 2,399 (14%) Guyana 345 (7%) Tanzania

VIA screen negative 4,717 (91%) Cote dIvoire 15,112 (86%) Guyana 4,682 (91%) Tanzania

Referred for large lesions 114 (28%) Cote dIvoire 365 (15%) Guyana 52 (15%) Tanzania

Treated with cryotherapy on same day as screening (SVA)* 193 (77%) Cote dIvoire 1,642 (84%) Guyana 258 (88%) Tanzania

Cryotherapy treatment postponed* 58 (23%) Cote dIvoire 302 (15%) Guyana 34 (12%) Tanzania

LEEP performed 0 (0%) Cote dIvoire 229 (63%) Guyana 0 (0%) Tanzania

Lost to advanced care follow-up 114 (100%) Cote dIvoire 136 (37%) Guyana 52 (100%) Tanzania

Returned for cryotherapy after previously postponing 32 (55%) Cote dIvoire 178 (59%) Guyana 6 (18%) Tanzania

Lost to cryotherapy treatment 26 (45%) Cote dIvoire 124 (41%) Guyana 28 (82%) Tanzania

* Denominator Guyana and Cote dIvoire: VIA screen positive Referred for large lesions suspect cancer cases. Denominator for Tanzania: VIA screen positive referred for large lesions

Data through Sep 2011

The Single Visit Approach

42% (150) of the VIA+ patients that were eligible for cryotherapy but were postponed NEVER returned for treatment

Results from a Multi-Country Cervical Cancer Screening Program for HIV-Infected Women
Conclusions:
HIV+ women were more likely to be VIA+ than HIV-/unknown women and HIV+ women were more likely to have larger lesions that were ineligible for cryotherapy 42% of women who were eligible for cryotherapy but postponed treatment never returned for treatment VIA/SVA is feasible from a programmatic standpoint and results in reduction of loss to follow-up as compared to screening requiring a subsequent visit

New directions for Jhpiegos Cecap Programs for PLWHA

Physician providers now being trained in LEEP for women with large lesions all 3 countries have LEEP services Data on ART and CD4 being collected to further refine screening and treatment protocols and inform guidelines on appropriate screening strategies and intervals identify correlations with lesion size Referral patterns further developed to ensure appropriate evaluation and management of women with large lesions or suspicious for cancer

Results from a Multi-Country Cervical Cancer Screening Program for HIV-Infected Women
Research Questions/Issues:
Will screening earlier in the course of HIV, when there is less immunosuppression, be associated with smaller and more treatable lesions? Will ART and associated immune reconstitution make a difference in rates of VIA positivity and lesion size? How will rapid HPV testing or other molecular screening strategies be best utilized as these become available and feasible in low resource settings? What models for training, implementation and data collection will be most effective for integration of cervical cancer screening for HIV+ women?