Cervical Cancer Prevention in Japan: Troubling Times

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1 PCC Melbourne 2015 Cervical Cancer Prevention in Japan: Troubling Times Sharon J. B. Hanley Department of Women s Health Medicine, Hokkaido University, Sapporo, Japan

2 Declaration (Based on ICMJE guidelines) I am on the executive board of the People's Campaign Against Female Cancers (PCAF) and a committee member of the Japanese Expert Board for the Eradication of Cervical Cancer. I have received lecture fees from Japan Vaccine and the Japanese Expert Board for the Eradication of Cervical Cancer. PCAF and the Japanese Expert Board for the Eradication of Cervical Cancer have received funding from Japan Vaccine and Merck Sharp and Dohme

3 Outline of Presentation 1. Burden of Disease 2. Cervical cancer screening in Japan 3. HPV vaccination in Japan 4. Conclusions

4 Cancer Incidence Rates in Japanese Women aged 20-39yrs 1 Cervix Includes carcinoma in situ Around 15,000 cases of cervical cancer annually 1 Around 3,500 deaths 1 Most common cancer in women of reproductive age 1Center for Cancer Control and Information Services, National Cancer Center, Japan

5 Comparison of Cervical Cancer Incidence and Mortality between Japan, the US and Australia Japan (2010) 1 US (2011) 2 Australia (2011) 3 Incidence Mortality

6 Cervical Cancer Screening in Japan 1 National screening programme established in late 1950s Local government became responsible for screening from 1984 Different areas have different subsidies Costs between $20-$30 with no subsidy Screening aged and interval changed in yrs 20yrs (no upper age limit) annually every 2 years Women can also get screened during annual work health check-up Not included in government figures Women also screened opportunistically (during pregnancy etc) Not included in government figures

7 Cervical Cancer Screening in Japan 2 Smear takers are gynecologists mostly men nurses/ midwives not allowed to take Pap smear stigma associated with single women going to a gynecologist (STI, unplanned pregnancy) not educated about the importance of screening in schools or university Primary screening using cytology with HPV testing for ASCUS triage Screening uptake around 25% in the local government programme around 40% including opportunistic screening no screening register

8 Recent Initiatives to Increase Screening Uptake Free Screening Coupons For women 25, 30, 35, 40, 45yrs 1 Center for Cancer Control and Information Services, National Cancer Center, Japan

Timeline of Events Leading up to Suspension of HPV Vaccine Recommendations in Japan October 2009 Cervarix licensed in Japan Gardasil in July 2011 March 8 th 2013 Asahi newspaper reports of 50 girls

9 Timeline of Events Leading up to Suspension of HPV Vaccine Recommendations in Japan October 2009 Cervarix licensed in Japan Gardasil in July 2011 March 8 th 2013 Asahi newspaper reports of 50 girls suffering from Chronic Regional Pain Syndrome (CRPS) and 100 absent from school. April 1st 2013 HPV vaccine included in the National Immunization Programme (NIP) Free for girls aged 12-16yrs May 19th 2013 Press conference by the Victims Support Group November 2010 Temporary fund launched for girls aged 12-16yrs. 50% national government, 50% local government March 10 th 2013 Adverse events reported on TV news April 13th 2013 Suginami local government announces budget for the next fiscal year. Includes compensation for a girl allegedly suffering from CRPS June 13 th 2013 WHO GACVS report released stating HPV vaccine safe. Not reported by Japanese media November 2011 Uptake rates of 1 st dose estimated at around 70% in the non-school (clinic)-based programme March 25th 2013 Press conference held by Victims Support Group showing girls suffering from walking disturbances and seizure May 16th 2013 First meeting of the Vaccines Adverse Reactions Review Committee (VARRC) June 14 th 2013 Second meeting of VARRC. Proactive recommendation of HPV vaccine suspended

10 HPV Vaccine Acceptance in Japanese Parents of Adolescent Girls (pre-controversy) Survey of 2100 parents with girls aged 10-14yrs (Sept-Dec 2010, 42% return rate) - 92% of mothers and fathers willing to vaccinate daughter if free - only 1.5% willing to pay the full price (between $ ) - 98% believed the vaccine was effective in preventing cervical cancer % thought the vaccine was safe, 54.7% not sure % thought the vaccine had no serious side effects, 49.6% not sure Correlates of HPV Vaccine acceptance - Recommendation from a physician (OR= 12.60, 95% CI ) - Recommendation from local health authority (OR= 27.80, 95% CI ) - Daughter s friends being vaccinated (OR= 6.53, 95% CI ) Hanley et al. Vaccine ;30(39): Hanley et al. Asian Pac J Cancer Prev. 2014;15(4):

11 What does the Suspension of HPV Vaccine Recommendations Mean? Ministry of Health Labour and Welfare (MHLW) directive advises prefectural governors not to actively recommend the vaccine, and to cease all vaccine promotion. Prefectural governors have to inform all health boards and medical professionals of this decision. BUT Health facilities are to continue to offer parents seeking the vaccine full support and facilitate vaccine access. Head of the special committee investigating these alleged adverse also stated "The decision does not mean that the vaccine itself is problematic from the viewpoint of safety" "By implementing investigations, we want to offer information that can make the people feel more at ease. -Decision not based on scientific evidence -Enormous confusion for public health officials, doctors and parents

12 Timeline of Vaccines Adverse Reactions Review Committee May 16th 2013 First meeting of the Vaccines Adverse Reactions Review Committee (VARRC) Rejects requests to remove the HPV vaccine from the NIP Dec 25th 2013 Third meeting of the Vaccines Adverse Reactions Review Committee (VARRC) June 14 th 2013 Second meeting of VARRC. Proactive recommendation of HPV vaccine suspended Members go on a 6 month fact finding mission Jan 20 th 2014 Fourth meeting of the Vaccines Adverse Reactions Review Committee (VARRC) Feb 26th 2014 Fifth meeting of the Vaccines Adverse Reactions Review Committee (VARRC) July 4 th 2014 Sixth meeting of the Vaccines Adverse Reactions Review Committee (VARRC)

13 Conditions of Interest Complex Regional pain Syndrome (CRPS) Chronic pain condition that normally affects one of the limbs, usually after injury or trauma needle trauma rather than constituents of vaccine Acute Disseminated Encephalomyelitis (ADEM) Rare autoimmune disease marked by widespread attack of inflammation in the brain and spinal cord. It is often triggered following a viral infection or vaccination (onset several days to 2 week after trigger) Guillain-Barré Syndrome (GBS) A disorder in which the body's immune system attacks part of the peripheral nervous system. The first symptoms include varying degrees of weakness or tingling sensations in the legs.

14 Taken from minutes of the VARRC meeting of Dec 25 th 2013 How do medically confirmed AEFI differ from reported cases? Drug Companies 2,753 reports of adverse effects (32.7/100,000 cases) Doctors Parents/ Guardian Victims Support Group Ministry of Education 863 cases 1457 cases 115 cases 147 cases 171 cases 2320 cases (26.1/100,000) Cases diagnosed as serious by a doctor 538 cases (6.4/100,000) Duplicate cases removed 62 cases 89 cases 128 cases 279 cases (3.3/100,000) Patients suffering from extensive pain and mobility disorders 130 cases (1.5/100,000) 111 cases (1.2/100,000)

15 Two teams appointed to medically evaluate victims Team 1 : Pain 11 institutions 85 cases Team 2 : Mobility disorders 6 institutions 32 cases

16 Time to Onset of Extensive Pain after Vaccination (n=97) 29 cases (30%) occurred within 24 hours (0.4/100,000 doses) 50 cases (50%) occurred within 2 weeks (0.6/100,000 doses) 61 cases (60%) occurred within 1 month (0.7/100,000 doses) All data 1.2/ 100,000 doses Time to onset of symptoms after vaccination Taken from minutes of the VARRC meeting of Dec 25 th 2013

17 Physical examinations suggested the pain was not organic in origin Yes N (%) No N (%) Yes N (%) No N (%) Swelling at injection site 1 (2) 59 (98) Hypoesthesia 2 3 (5) 52 (95) Pressure pain at injection site 3 (5) 57 (95) Strange sensation upon touch 2 (4) 64 (96) Redness at injection site 1 (2) 58 (98) Allodynia 3 4 (6) 58 (94) Physical paralysis 4 (6) 59 (94) Brisk reflex 1 (2) 44 (98) MMT MMT 3 2 Fever (above 36.8?) 6 (12) 46 (88) MMT 4 2 Swollen joints 3 (5) 62 (95) 1 Manual Muscle Testing (MMT) 0= none, 1= trace, 2= poor, 3= fair, 4= good, 5= normal 2 partial loss of sensitivity to sensory stimuli. 3 the experience of pain from a non-painful stimulation of the skin Taken from minutes of the VARRC meeting of Dec 25 th 2013

18 Time to Onset of Mobility Disorders after Vaccination (n=33) 11 cases (30%) occurred within 24 hours (0.1/100,000 doses) 19 cases (60%) occurred within 2 weeks (0.2/100,000 doses) 23 cases (70%) occurred within 1 month (0.25/100,000 doses) All data 0.4/ 100,000 doses Time to onset of symptoms after vaccination Taken from minutes of the VARRC meeting of Dec 25 th 2013

19 Onset and Duration of Reported Extensive Pain and Mobility Disorders by Group All cases Data from drug companies/ medical institutions 130 cases (1.5/100,000) Data from parents, victims group, Ministry of Ed 111 cases (1.2/100,000) Combined Total 241 cases (2.7/100,000) Onset unknown/ Duration >3mths 69 cases (0.8/100,000) 57 cases (0.6/100,000) 126 cases (1.4/100,000) Within 1mth/ >3mths 44 cases (0.5/100,000) 33 cases (0.4/100,000) 77 cases (0.9/100,000) Within 2wks/ >3mths 27 cases (0.3/100,000) 16 cases (0.2/100,000) 43 cases (0.5/100,000) Within 24hours/ >3mths 18 cases (0.2/100,000) 9 cases (0.1/100,000) 27 cases (0.3/100,000) Taken from minutes of the VARRC meeting of Dec 25 th 2013 Medically confirmed unconfirmed

20 Frequency of Extensive Pain and CRPS in the Literature 1 (0.3 for females only) 2 3 Rates lower than other cohort data Needle trauma not vaccine constituents to blame 4 1 5yr data, n=26,000,000, all ages (>20yrs) and gender 2 Girls aged 12yrs, Canada, Jastaniah WA et al., J. Pediatr, Data from VARRC, Dec 25 th 2013, Pain including CRPS occurring within 4 weeks of vaccination 4 Girls aged 10-19yrs, De Mos et al., Pain 2007 Per 100,000 people 100,000 doses

21 Frequency of Mobility Disorders ADEM/GBS in Japan Rates lower than historical data and also lower than other vaccines 3 1 VARRC data from February 28 th ADEM/GBS any time after vaccination, cause unknown limited to onset within 4 wks after vaccination 3 Hara Toshiro, Nihonrinsho 71:5, 2013, Sato Toyokazu, MHLW report of specified diseases 1997 Per 100,000 people 100,000 doses

22 Significantly Higher Reporting of AEFI with the Bivalent Vaccine Immediately after Vaccination (Different adjuvant) Reported AEFI within 7 days of vaccination Lethargy Muscle pain Swelling at injection site redness pain Cervarix (n=524) 49.8% (95%CI: )) 27.6% (95%CI: ) 36.5% (95%CI: ) 44.3% (95%CI: ) 92.9% (95%CI: ) Gardasil (n=524) 39.8% (95%CI: )) 19.6% (95%CI: ) 21.8% (95%CI: ) 25.6% (95%CI: ) 71.6% (95%CI: ) P Value P=0.001 P=0.003 P<0.001 P< cases (0.3/100,000) chi squared participants : women aged 18-45yrs Einstein MH et al., Hum Vaccine 2009

Frequency of Reported Chronic Pain and Mobility Disorders by Vaccine Type Cervarix 1 Gardasil 2 Serious cases Onset unknown/ Duration >3mths 6.0/100,000 ) (425 cases) 1.3/100,000 (94 cases) 6.

23 Frequency of Reported Chronic Pain and Mobility Disorders by Vaccine Type Cervarix 1 Gardasil 2 Serious cases Onset unknown/ Duration >3mths 6.0/100,000 ) (425 cases) 1.3/100,000 (94 cases) 6.9/100,000 (128 cases) 1.9/100,000 (36 cases) 1 7, doses administered 2 1, doses administered Within 1mth/ >3mths 0.7/100,000 (50 cases) 1.0/100,000 (19 cases) All cases medically confirmed Within 2wks/ >3mths Within 24hours/ >3mths 0.5/100,000 (33 cases) 0.2/100,000 (16 cases) 0.6/100,000 (11 cases) 0.1/100,000 (2 cases) No statistical difference between vaccines (p<0.3)

Comparison of AEFI by Country per 100,000 doses AEFI All 26.1 53.

3 Specific Conditions Serious only Serious only Serious/non-serious

4 0.3 Hypersensitivity response 0.3 0.2 - - Anaphylaxis 0.2 0.03 1.

04 - - Venous thrombosis 0 0.2 - - CRPS 0.1-0.1 - Death 0.01 0.

24 Comparison of AEFI by Country per 100,000 doses AEFI All Serious Specific Conditions Serious only Serious only Serious/non-serious Serious only Local reaction Fainting Hypersensitivity response Anaphylaxis GBS Transverse Myelitis Venous thrombosis CRPS Death Extensive pain not related to injection site Total doses administered 8.900,000 23,000,000 6,000,000 7,700,000

25 Timeline of Vaccines Adverse Reactions Review Committee May 16th 2013 First meeting of the Vaccines Adverse Reactions Review Committee (VARRC) Rejects requests to remove the HPV vaccine from the NIP Dec 25th 2013 Third meeting of the Vaccines Adverse Reactions Review Committee (VARRC) June 14 th 2013 Second meeting of VARRC. Proactive recommendation of HPV vaccine suspended Members go on a 7 month fact finding mission Jan 20 th 2014 Fourth meeting of the Vaccines Adverse Reactions Review Committee (VARRC) Conclude there is little evidence to suggest a causal link between chronic pain and the HPV vaccine Feb 26th 2014 Fifth meeting of the Vaccines Adverse Reactions Review Committee (VARRC) July 4 th 2014 Sixth meeting of the Vaccines Adverse Reactions Review Committee (VARRC)

26 Timeline of Vaccines Adverse Reactions Review Committee May 16th 2013 First meeting of the Vaccines Adverse Reactions Review Committee (VARRC) Rejects requests to remove the HPV vaccine from the NIP Dec 25th 2013 Third meeting of the Vaccines Adverse Reactions Review Committee (VARRC) June 14 th 2013 Second meeting of VARRC. Proactive recommendation of HPV vaccine suspended Members go on a 7 month fact finding mission Jan 20 th 2014 Fourth meeting of the Vaccines Adverse Reactions Review Committee (VARRC) Conclude there is little evidence to suggest a causal link between chronic pain and the HPV vaccine Feb 26th 2014 Fifth meeting of the Vaccines Adverse Reactions Review Committee (VARRC) July 4 th 2014 Sixth meeting of the Vaccines Adverse Reactions Review Committee (VARRC) The committee continues to prepare the final report

27 Uptake rates % Uptake rates for HPV vaccine before and after suspension of proactive recommendations: Sapporo, Japan (as of March 31 st 2014) 90.0 Eligible for free vaccination before suspension of proactive recommendation Eligible for free vaccination after suspension of proactive recommendation n=8598 n=8267 n=8165 n=8002 n=7977 n=7731 n= yrs 17yrs 16yrs 15yrs 14yrs 13yrs 12yrs Dose 1 Dose 2 Dose 3 Number in cohort and age Hanley et al. Lancet 2015

28 What has happened since July 4 th? Findings of the group in charge of investigating mobility disorders published in the English journal of the Japanese Society of Internal medicine A case series No control group Relies on parental recall bias also A heterogeneous, opportunistic sample of patients No case definition Eclectic range of symptoms (>13) Extensive variability between vaccination and onset of symptoms; 5.47 months (±5 months)

29 HANS: A new syndrome has been proposed! Brain Microglia Activating Syndrome ASIA AS HANS Collaborative research with -Denmark -Russia -Israel CFS Fibromyalgia ASIA= Autoimmune syndrome induced by adjuvants HANS= Human papillomavirus vaccination associated with neuropathic syndrome CFS= Chronic fatigue syndrome

Human papillomavirus vaccination associated with neuropathic syndrome (HANS) Ⅰ Prerequisite Ⅱ Major Criteria Ⅲ Minor Criteria Exclusion criteria Judgment Criteria 1.

30 Human papillomavirus vaccination associated with neuropathic syndrome (HANS) Ⅰ Prerequisite Ⅱ Major Criteria Ⅲ Minor Criteria Exclusion criteria Judgment Criteria 1. Occurs after HPV vaccination (no time limit regarding onset of symptoms ) 2. No distinct physical or mental abnormalities before vaccination 1. Widespread physical pain 2. Joint pain and/or joint inflammation 3. Chronic fatigue: lasting 6 weeks or more, striking physical mental fatigue impairing daily life compared to before vaccination 4. Neurological symptoms : 2 or more from those listed below Headache, decreased mental state, convulsions, involuntary movements, paralysis, cognitive symptoms, numbness, visual impairment 5. Psychogenic and mental symptoms: 1 or more from those listed below Delirium, hypersomnia, drowsiness, breathing difficulties, weakness, environment sensitivity 6. Abnormal findings on brain imaging: SPECT, MRI, PET etc. 1. Menstrual abnormalities 2. Autonomic defects Orthostatic abnormalities, tachycardia, palpitations, feel cold, clamminess, impaired skin circulation 3. Abnormalities in spinal fluid Diagnosis of juvenile idiopathic arthritis, Lupus or other connective tissue disease HANS =Ⅰ(1+2)+Ⅱ(3 or more items), or Ⅰ(1+2)+Ⅱ(2 items)+3(one or more items)

31 Cervical Cancer incidence and mortality are increasing in young Japanese Women Screening uptake is poor Summary of Presentation HPV Vaccine introduced into the Japanese NIP from April 2013 The Vaccines Adverse Reactions Review Committee (VARRC) suspended proactive recommendation for HPV vaccine in June 2013, but continued to keep the vaccine in the NIP In January 2014 it concluded there was little evidence to suggest a causal link between chronic pain and the HPV vaccine Vaccine uptake has dropped from over 75% to less than 1% As of February 2015, proactive recommendation has not been reinstated

32 Thank you for your kind attention

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