1. Cervical Cancer and HIV: Interactions and Interventions Jean R. Anderson, M.D. Jhpiego, an affiliate of Johns Hopkins University The Johns Hopkins University School of Medicine

2. Cervical Cancer  Latest data on cervical cancer incidence and mortality (GLOBOCAN 2008, IARC*):  Globally 529,512 cases diagnosed per year: –86% of all cases (n=453,032) in developing world  Globally 274,967 deaths: –88% of all deaths (n=241,818) in developing world  Mortality to incidence ratio:  Developed countries: 36–43%  Developing countries: 54–80% 2 *www.iarc.fr/globocan2008

3. Globocan 2008—Most Frequent Cancers in Women in Africa* 3 *www.iarc.fr/globocan2008

4. Additional Burden in Africa: HIV/AIDS HIV incidence in Africa (UNAIDS 2010) Cervical cancer incidence in Africa (Globocan 2008, IARC) 4

5. HIV and Cervical Cancer  Studies have shown that among HIV-positive women, there is a consistently higher incidence of:  Human papillomavirus (HPV) infection  Persistent HPV infection with high-risk types  Infection with multiple types of HPV  Cervical cancer precursors (cervical intraepithelial neoplasia [CIN] or squamous intraepithelial lesion [SIL])  Cervical dysplasia tends to involve a larger area of the cervix in the setting of HIV infection  Cancer registry linkage studies have shown significant increase in cervical cancer, particularly where women live longer due to access to ART 5

6. Source: Palefsky. Curr Opin Oncol 2003. +++ ++ +/- 6

7. Alternatives to Cytology: Visual Inspection with Acetic Acid (VIA)  Meta-analysis of 26 studies (Int J Gynecol Obstet 2011;113:14) in which VIA was performed on asymptomatic women who underwent confirmatory testing with a disease threshold of CIN 2 plus reported:  Sensitivity of 80% (range 79–82%)  Specificity of 92% (range 91–92%)  Positive predictive value of 10%  Cluster-randomized trial in India (Lancet 2007;370:398):  31,343 screened with VIA vs. 30,958 controls, 30–59 years old, 7-year follow-up  VIA-positive received colposcopy/biopsy and cryotherapy at same visit with colposcopy impression low-grade SIL/high-grade SIL  VIA associated with 24% reduction in cervical cancer (Stage II or worse) incidence and 35% reduction in cervical cancer mortality  Safe, feasible and acceptable in multiple studies  Can be done by trained nurses/midwives  Inexpensive  Allows treatment at same visit 7

8. Alternatives To Cytology: HPV Testing  Cluster randomized trial in India  4 arms: HPV (hybrid capture), VIA, cytology, standard of care (no screening); >2,700 women 30–59 years in each arm with 8-year follow-up  Positive results: colposcopy/biopsy, treatment (cryotherapy or loop electrosurgical excision procedure [LEEP])  HPV testing associated with approximately 50% reduction in detection of advanced cervical cancer and cervical cancer deaths vs controls; no significant difference for VIA, cytology Source: NEJM 2009;360:1385. 8

9. Target for Screening and Flow Pattern VIA 30–50 Years HIV-Positive—at Any Age FP/MNCH, OPD, Gyn, ART Clinic Negative Positive Follow-Up 3 – 5 Years (HIV-) Follow-Up 1 Year (HIV+) Treat Immediately Cryotherapy Refer/Treat with LEEP Repeat VIA after 1 Year 9

10. VIA by Total and HIV-Infected Women and Treatment Rates 10 Country Total No. of New Women Screened with VIA/ % Who Were HIV+ Total No. (%) of Women Who Were VIA+ No. (%) of HIV+ Women Who Were VIA+ No. (%) of Women VIA+ Treated with Cryo on the Same Day (Single Visit Approach) Setting Time Period Guyana19,934/ 8% 2,529 (13%) 258 (16%) 1,813 (84%) HIV Care General Medical Clinic 1/09– 3/12 Côte d’Ivoire14,338/ 66% 960 (7%) 810 (9%) 460 (74%) HIV Care10/09– 9/13 Tanzania26,065/ 28% 2,021 (8%) 884 (12%) 1,660 (94%) HIV Care C&T 4/10– 9/13 Mozambique72,818/ NA 4,990 (6.8%) 897 (17.9%) 3,333 (66.7%) Family Planning 4/11– 9/13 Zambia (preliminary results) 386/ 13% 23 (6%) 4 (8%) 19 (100%) DOD9/13 Burkina Faso10,982/ 4% 965 (9%) 104 (22%) 508 (65%) OPD9/10– 8/13

11. Cervical Cancer VIA Screening and Treatment Outcomes for 3 Countries, January 2009–March 2012* 11 Returned for cryotherapy after previously postponing 42 (52%) Côte d’Ivoire 186 (55%) Guyana 6 (18%) Tanzania Lost to cryotherapy treatment 39 (48%) Côte d’Ivoire 150 (45%) Guyana 28 (82%) Tanzania *Côte d’Ivoire began in October 2009 and Tanzania began in April 2010. Suspect cancer cases detected and referred 50 (0.7%) Côte d’Ivoire 108 (0.5%) Guyana 178 (2%) Tanzania VIA screen positive* 519 (7%) Côte d’Ivoire 2,529 (13%) Guyana 532 (7%) Tanzania VIA screen negative 6969 (92%) Côte d’Ivoire 17,297 (87%) Guyana 6,739 (90%) Tanzania New women screened 7,538 Côte d’Ivoire 19,934 Guyana 7,449 Tanzania Referred for large lesions 159 (31%) Côte d’Ivoire 381 (15%) Guyana 82 (15%) Tanzania Treated with cryotherapy on same day as screening (SVA) 279 (78%) Côte d’Ivoire 1,813 (84%) Guyana 416 (92%) Tanzania LEEP performed 45 (28%) Côte d’Ivoire 239 (63%) Guyana 6 (7%) Tanzania Lost to advanced care follow-up 114 (72%) Côte d’Ivoire 142 (37%) Guyana 76 (93%) Tanzania Cryotherapy treatment postponed 81 (23%) Côte d’Ivoire 336 (16%) Guyana 34 (8%) Tanzania

12. Initial Results from a Multi-Country Cervical Cancer Screening Program for HIV-Infected Women  Summary of study:  VIA/SVA for cervical cancer prevention in Côte d’Ivoire (n=7,538), Guyana (n=19,934) and Tanzania (n=7,449)  Services provided by trained nurses/midwives at HIV care and treatment sites and general health facilities  Key results:  In all 3 countries, HIV-positive women were more likely to be VIA-positive than HIV-negative/unknown women  In all 3 countries, HIV-positive women who were VIA-positive were more likely to have large lesions (occupying >75% cervix) and therefore ineligible for cryotherapy  85% of eligible women had same-day treatment with cryotherapy; of those who postponed, 48% did not return for treatment 12 Source: Anderson J, Lu E, Wysong M, Kibwana S, Estep D, Varallo J, Toure K, Giattas M, for Jhpiego.

13. Lessons Learned  Promote country ownership  Implement sustainable, organized screening for scale-up  Conduct monitoring and assessment  Build capacity  Maintain quality of care 13

14. Research Priorities  What are the optimal screening strategies for cervical cancer precursors in setting of HIV?  Potential role of self-collection  Role of HPV-DNA testing  What are the optimal treatment methods for cervical cancer precursors in setting of HIV?  Does screening or treatment effectiveness vary by CD4/CD4 nadir or ART status?  What are the determinants of recurrence and what are best strategies to identify recurrences? 14

15. Research Priorities (cont.)  How can recurrences be prevented?  What is the role of male circumcision in cervical cancer prevention (and programmatic implications)?  What are effects of treatment (cryotherapy vs. LEEP, others?) on HIV shedding and what are the determinants?  What are the most effective strategies to incorporate cervical screening and treatment into HIV care?  Models of integration  Systems issues  Quality control: training, pathology, etc. 15

16. Summary  Cervical cancer is a leading cause of morbidity and mortality in limited-resource countries  HIV infection is associated with higher incidence of cervical cancer and its precursors and this association persists in the era of effective ART  Alternatives to cytology, such as VIA, are critical to ensure adequate coverage and appropriate interventions for cervical cancer screening and prevention in the setting of HIV, but several key research questions remain 16