Vaccination in a couple in which one of the members has GW or any other HPV lesion (CIN)?

principles of HPV vaccination Some derived from Phase III trials Some are based on clinical judgement / research HPV vaccines have no contraindications by age, gender or clinical status except pregnancy or specific allergies to the vaccine products Benefits (non-quantified) can always be predicted because HPV infection with all 4 or 9 HPV types is very rare Reinfections with same type can occur and prevented by vaccination Vaccination of HPV+ individuals is safe Vaccination of immune suppressed individuals is safe and effective Individuals with any previous HPV lesions are a high risk group that should benefit from vaccination Individuals with current HPV lesions are a high risk group for transmission and vaccination may reduce such risk Discussion of individual cases can easily adapt to these principles

Vaccination in a couple in which one of the members has GW or any other HPV lesion (CIN)? Assumption the “case” is infectious Partner is or can be contaminated Some protection offered if both are vaccinated BEWARE: vaccines are not therapeutic and there is no effective treatment for HPV. HPV positive individuals (GW or CIN or HPV+) need to be surveilled until clearance

Question: GW recurrence reduction after vaccination?

Outcome: Genital warts All data we have includes Episodes of GW diagnosis (i.e. Relative Fraction) mostly representing combinations of first and subsequent diagnosis. Best example is RRP where all recurrent episodes are self-reinfection

AUSTRALIA: POPULATION IMPACT ESTIMATES ON GENITAL WARTS 1. Read et.al., Sex Transm Infect 2011; 87:544e547. doi:10.1136/sextrans-2011-050234 Women <21: 18.6-1.9%, MSW: 22.9-2.9% Decline in nearly 90% in both men and women <21 National HPV vaccination programme Declines in under 21 years of age: women from 18.6% to 1.9% heterosexual men from 22.9% to 2.9% Around 93% reduction of GW – this has been seen also in other countries 6

Outcome: Recurrent respiratory papillomatosis in infants

All RRP cases were born to non-vaccinated mothers Hpv Vaccination impact on respiratory papillomatosis incidence in Australia between 2012 and 2016 Prospective surveillance of the population. Linkage to vaccination records All RRP cases were born to non-vaccinated mothers Evidence from case reports: Vaccination of RRP cases before surgery reduces the recurrence rates and the clinical severity of the cases 0.32 / 100,000 0.04 / 100,000 8-fold reduction

Question: use of HPV vaccines in males older that 26 years of age?

EMA: HPV vaccine recommended ages 9+ for males and females UK, others: vaccination of MSM up to age 45

Quadrivalent HPV vaccine efficacy studies in men Vaccine efficacy against EGL, (mostly GW) in men Vaccine efficacy against anal intraepithelial lesions in MSM 90.6% (70-98) 77.5% (40-93) Giuliano et al. NEJM 2011 Per protocol cohorts Palefsky et al . NEJM 2011 Increase protection of women further by interrupting transmission Protect vaccinated males against HPV-induced cancers

Other (non-sexual) ways of HPV transmission? Very limited and poorly documented HPV DNA in fingernails HPV DNA in fomites Unclear if these can activate transmission BEWARE: HPV detection is not necessarily a marker of recent exposure to HPV. Reactivation of latency status following other environmental exposures is documented (i.e. pregnancy, menopause, other…)

Is HPV screening and typing a requirement before (and conditional to) vaccination? In Iran women are not vaccinated as adolescents and first visit is with gynecologist at 20+ Phase III trials have all included women irrespective of HPV status HPV prognosis not altered by vaccination HPV positive women do not experience adverse reactions Protection against types other than the prevalent one is high Precaution is that HPV+ need to be under surveillance until clearance

HPV vaccine efficacy in mid-adult women Outcome 4vHPV (to age 45) 2vHPV (to age 55) ‘per-protocol’/‘according-to-protocol’ ( HPV negative) 6M Persistent infection VE: 89.6% (95%CI 79.3–95.4) VE: 91.4% (95%CI 79.4-97.1)* ‘intention-to-treat’/‘total-vaccinated-cohort’ (irrespective of HPV) VE: 49.0% (95%CI 35.5–59.9) VE: 60.0% (95% CI 46.4‑70.4)* Baseline seropositive but HPV-DNA-negative (previous infection) 6M persistent infection (≥ 1 dose) VE: 66.8% (95% CI 3.8‑90.5) NR 6M Persistent infection + (3 doses) VE: 86.4% (30.1–99.0) Bold blue: statistically significant under trial conditions *: updated at month 84

Is there any need to stop HPV prevention until G9 is available in Iran? Prevention is already achieved a very high level using the first generation vaccines Achieving high coverage of the vaccination program takes time Delaying vaccination because of the future arrival of another broad spectrum vaccine is ethically debatable

HOW TO BEST PROTECT WOMEN AND GIRLS TODAY Enter HPV vaccines into the national routine vaccination program of the country. Most likely focusing on school-based programs Use currently available vaccines ( 2-dose regimes) Focus all organizational efforts to achieve high coverage of the target population Consider wider catch-up populations ( i.e. to age 26) Consider male vaccination as well Coordinate with the screening programs

Is there any need to provide a booster dose after 10 years? Phase II / III trials have reported high AB titers up to 12 years (above natural infection and plateau) Modeling duration of AB titers predict plateauing up to 20+ years Clinical follow up of some cohorts have not documented any “vaccine failure case” No predictions / plans for vaccine boosters are in place

AB PROFILE OF LESS THAN THREE DOSES AB PROFILE OF LESS THAN THREE DOSES. HPV16 (A) AND HPV18 (B) SPECIFIC ANTIBODY GEOMETRIC MEANS. COSTA RICA TRIAL 3 2 2 1 Safaeian M, et al. Cancer Prev Res; 6(11); 1242–50. Profile maintainned at 7 years No cases of HPV 16/18, not even in the one dose arm R

Pregnancy between dose 2 and dose 3. Shall we wait? Yes postpone third dose until end of pregnancy

Two-dose schedule (0-6) and a women misses the second dose The interval between dose 1 and 2 in girls before 15 years of age is recommended to be of at least 6 month and can be extended up to 12 months. Therefore within the 6-12 month window no need to reinitiate the program

Thank you for your interest shukran