HPV Management in Special Populations MELISSA KOTTKE, MD, MPH, MBA Disclosures Merck, Nexplanon trainer CSL Behring, Consultant Evofem, Advisory Board Most treatment options for HPV in special populations are off-label. Evidence will be presented when available. 1
Objectives Describe the impact of immune compromise and HPV infection and vaccination Manage condyloma in adolescent patients with immune compromise (ex. HIV, organ transplant) Discuss management of condyloma for the young pediatric patient Case Your second year resident is seeing a 14 year old girl referred to your PAG clinic for management of HPV. She has a history of a renal transplant when she was 3 years old. Your resident comments that she remembers reading something about girls who are immunocompromised being at increased risk from HPV 2
Immunology of HPV infection In an immune competent person, cellmediated immunity helps to support regression of HPV lesions and control of latent infection 3
What conditions can lead to immune compromise? Pi Primary Immune deficiency i Over 250 primary immune deficiencies (b cell, t cell, complement, phagocytosis) recognized by the WHO Extent of immune compromise can vary widely Secondary immune deficiency HIV Solid organ transplant Hematopoetic stem cell transplant Immunosuppressive and immune modulating drugs Autoimmune inflammatory conditions Inflammatory Bowel Disease (IBD) Systemic Lupus Erythematous (SLE) Juvenile Idiopathic Arthritis (JIA) Immunosuppressive and immune modulating drugs Mechanism of action of immunosuppressive agents Drug Mechanism of action Immune consequences Steroids Inhibition of gene transcription for secretion of inflammatory cytokines Reduction of leukocyte migration, phagocytic function of neutrophils and monocytes, and T-cell function Azathioprine, 6- Mercaptopurine Cyclosporine, tacrolimus Anti-TNF agents Purine antimetabolite Inhibition of cytosolic enzyme calcineurin Selective inhibition of cytokines Binding to TNF-alpha Apoptosis of T lymphocytes Suppression of cell-mediated immunity Inhibition of inflammatory cells; reduction of inflammatory proteins. 4
Immune compromise and HPV: increased rates Increased rates of HPV infection HIV patients have a prevalence of HPV infection as high as 31-57% Incidence of anogenital HPV infection is increased 17-fold in immunosuppressed renal transplant patients Immune compromise; increased severity and duration Increased severity Frequently infected with multiple HPV types For those with condyloma Have a higher HPV viral load within condyloma Have a higher prevalence of HR HPV-16 Increased duration Reduced cytotoxic T- lymphocyte reactivity to HPV oncoproteins E6 and E7 leads to impaired ability to clear HPV Altered cytokine release in epithelium allows for reactivation of latent HPV 5
Gynecologic manifestations of HPV Benign Condyloma Accuminata (CA) By far most common HPV 6, HPV 11 primarily Giant CA: Buschke-Lowenstien Tumor (BLT) Intermediate malignant potential Premalignant & Malignant Cervix Vulva Vagina Anus HPV 16, HPV 18 Case Your patient had a renal transplant for a Wilm s tumor. On exam: Add photo here She is taking Prednisone and Tacrolimus 6
Assessment She has been dating male partners since she was 13 Patient denies having penile-vaginal sexual intercourse You review safe sex practices Lui, Sexual Health 2016 7
What if she was 5 years old? The incubation period can vary widely from months to years Vertical transmission is possible, but not likely for this age Physical evaluation for additional signs of sexual abuse and mandatory reporting should be performed For younger girls, obtain a detailed history of HPV diagnoses in mother, family and caregivers Treatment options for young girls There are no FDA approved treatment options for patients under 12 years old Treatment is driven by patient-family situation and preferences 8
Considerations Spontaneous regression of CA can occur in those with IC There is no way to predict who will have a regression May lead to larger or more numerous CA May be more difficult to treat No clear first line therapy Personalized approach number, size, morphology, degree of keratinization, locations of the warts; patient preference; provider experience; and potential side effects. Treatment is not aimed at removal of HPV infection, rather removal of lesion or increasing immune response. HPV testing is not recommended Gromley, J Am Acad Derm, 2012 Patient Applied Treatments Drug Dosage Instructions Side effects Imiquimod 5% cream Apply qhs 3/week x 16 weeks max Wash off in am Podofilox 0.5% solution Apply twice a day for three days, followed by four days of no therapy Redness, irritation, induration, ulcerations, and vesicles Mild to moderate pain or local irritation possible Green Tea Sinecatechins/Poly phenol E (Approved in those 18 and over) Gromley, J Am Acad Derm, 2012 15% ointment Apply 3 times daily (0.5 cm strand of ointment to each wart) using finger to ensure coverage. Use no longer than 16 wks. Do not wash after use. Erythema, itching, burning, ulceration, edema, and rash 9
Patient Applied Treatments Drug Clearance Recurrence Cost Imiquimod 40-70% 9-19% $$ Podofilox 37-88% 4-38% $ Sinecatechins/ Polyphenol E 54-65& 5-12% $$$ Gromley, J Am Acad Derm, 2012 Use of Imiquimod in IC patients Clearance may happen in 8-10 weeks or sooner. Effective in those with IC. For those with HIV, clearance was not related to CD4 count No systemic immunostimulatory effects and does not have adverse effects on grafted organs in systemically immunosuppressed organ transplant patients Gromley, J Am Acad Derm, 2012 10
Back to case Patient elects for Imiquimod and has clearance in about two months. Add photo She returns one year later with return of her CA Provider Applied Treatments Drug Dosage/approa Instructions Side effects ch Cryotherapy Using liquid nitrogen or cryoprobe Repeat q 1-2 weeks, as needed Pain, necrosis, ulceration, blistering Trichloroacetic acid (TCA) 50%-90% Apply small amount, allow to dry Local irritation, burning pain Low viscosity, can easily spread to adjacent tissue Pain, bleeding, may require anesthesia Surgical removal Tangential Single visit Pain, bleeding, may scissor/shave, curettage, electrosurgery, laser management Gromley, J Am Acad Derm, 2012 11
Patient Applied Treatments Drug Clearance Recurrence Cost Cryotheraphy 27-88% 21-29% Varies by site and extent of lesion Surgical removal 35-72% 19-29% Varies by site and extent of lesion Gromley, J Am Acad Derm, 2012 Additional treatment options More studies are need on the following: Cidofovir, 1% cream has been used with some success in special populations, including IC and pediatric populations Cimetidine 30-40 mg/kg/day x 30 months Gromley, J Am Acad Derm, 2012, Culton Pediatric Annals, 2009, Thornsbury, JPAG 2012 12
Case Patient elects for cryotherapy Number and size of lesions at presentation are associated with achieving clearance (fewer and smaller more likely) Recurrence is common Combined approaches with provider and patient applied therapies may be valuable Her mom asks about whether she needs a pap smear Screening Panel on Opportunistic Infections in HIV infected adults and adolescents recommends age based screening. Initiate pap smears at initiation of sexual activity regardless of mode of HIV transmission. No later than 21 years For those with an initial HIV diagnosis < 30 years old, pap in that first year and annually. If three consecutive normal results, may space out screening to every three years Co-testing not recommended <30 years May be reasonable in other IC populations ACOG practice bulletin 157, January, 2016 13
Case continued She reports in private that before the most recent warts showed up, she and her boyfriend started having sex. STI screening Discuss initiating pap screening Neither she nor her mother remember if she got HPV vaccination Case Secondary prevention Condoms HPV Vaccine Will a vaccine be safe? Will it be effective? 14
3/31/2016 HPV Vaccine contraindications Contraindications: Allergy Pregnancy Not a live vaccine http://www.cdc.gov/vaccines; accessed 2.28.16 Vaccination with Vaccine Like Particles PRCH, 2008 15
Antibodies prevent infection Papillomavirus = Antibodies No DNA strands can escape the capsid PRCH, 2008 Vaccination for those with HIV One study by Levin, et al, found that vaccination was safe and immunogenic in HIV-infected children aged 8 to 11 years. Serum antibodies to HPV6 and 18 were 30% to 50% lower than in historic age-matched immunocompetent controls. At 18 months after the third dose of vaccine, 94% to 99% had antibody to HPV6, 11, and 16, however, only 76% had antibody to HPV18. Levin, AIDS, 2010 16
Vaccination for those with transplant The vaccine was safe and well tolerated. Four weeks after last dose, response: HPV 6 63.2% HPV 11 68.4% HPV 16 63.2% HPV 18 52.6% Factors associated with reduced immunogenicity vaccination early after transplant (p = 0.019), having a lung transplant (p = 0.007) having higher tacrolimus levels (p = 0.048) At 12 months, significant declines in antibody titer for all types, but number who were seropositive did not change Kumar, et al, Am J of Transplan, 2013 Vaccination for those with autoimmune disorders Pellegrino, Vaccine Volume 33, Issue 30, 9 July 2015, Pages 3444 3449 17
3/31/2016 Vaccination recommendations in children with HIV HPV vaccine recommendations in those undergoing transplant/chemo Temkin, Cancer 2015;121:3395-402. 18
Case wrap up and summary She will receive HPV vaccination She saw resolution of her CA Pap screening (without HPV testing) was initiated and follow-up per ASCCP guidelines HPV vaccination should be offered to IC and other special populations Ideally prior to sexual exposure No single CA treatment is recommended as first line Recurrence is common 19
Thank you 20