1. HIV & HPV Co-infections: Clinical Presentation & Management
Sara Lowe MBChB MRCP
Margaret Pascoe MBChB

2. Presentation Outline HIV and HPV
HPV-related disease in a HIV-infected cohort
Case studies
Vulvar intraepithelial neoplasia and HIV
HPV prevention

3. Human Papilloma Virus and HIV
1 in 6 new cancer diagnoses worldwide attributable to an infectious pathogen1
HPV causes 1/3 of infection-associated cancers
Frequency of HPV-associated cancers increasing at anatomical sites other than the cervix (vagina, vulva, anus, & oropharynx), where validation of screening strategies is lacking2
HPV associated disease more common in HIV-infected individuals
1. de Martel C Lancet Oncol 2012
2. Chaturvedi AK. Adolesc Health 2010

4. HPV-related Disease in an HIV Cohort
Newlands Clinic provides comprehensive care & treatment for 5500 patients, of whom 60% are female
Sexual reproductive health services including cervical cancer screening, Family Planning, STI diagnosis & treatment provided by trained nurses & consultants
Biopsies, cryotherapy, LEEP, antibiotics
Partner notification & treatment

5. HPV-related Disease in an HIV Cohort
2015 at Newlands Clinic:
Genital warts 15 patients/week
2 cases of VIN II
5 cases of VIN III
2 cases of vulvar cancer
4 penile squamous cell carcinoma

6. Case Study 1 Mrs PN 47 year old female
11 years on ART, currently on 2nd line: ABC/3TC/ATV/r
CD4 count 475, VL < 20 cp/ml
Presenting complaint: 6 month history of genital ulcers treated with Acyclovir
Background GU history: genital warts, VIAC +ve → LEEP

7. Case Study 1
Vulval biopsy April high grade dysplasia (VIN III)

8. Case Study 2 Mrs RD 66 year female
11 years on ART, currently on 1st line: TDF/3TC/NVP
CD4 count 291, VL < 20cp/ml
Presenting complaint: 1 month history of vulval sore
Background GU history: Treated for BV & vaginal candidiasis

9. Case Study 2
Vulvar biopsy: HPV, focal VIN III

10. Case Study 3 Mrs IL 42 year old woman
84 weeks on ART, currently on 1st line: TDF/3TC/EFV
CD4 697, VL < 20 cp/ml
GU history:
- Chronic vulvar sores rx with Acyclovir for +/- 2 years
- VIAC +ve: LEEP Nov 2013 (CIN III) & May 2014 (CIN II)

11. Case Study 3
Vulval biopsy: Full thickness dysplasia, carcinoma-in-situ (VIN III)

12. Case Study 4 Mr BM 34 year old male
2 years on ART, currently on 1st line: TDF/3TC/EFV
CD4 80, VL
Treated for genital warts for> 1 year
Also treated for genital ulcer disease

13. Case Study 4
Biopsy: Moderately differentiated squamous cell carcinoma

14. Case Study 5 Mr HN 52 year old male
8 years on ART, currently on 1st line: TDF/3TC/EFV
CD4 210, VL < 20 cp/ml
Genital ulcer for +/- 3 months
Urethral discharge
Was treated with Acyclovir, Kanamycin & Doxycycline

15. Case Study 5
Biopsy: poorly differentiated squamous cell carcinoma

16. Life changing outcomes
Post-penectomy

17. Lessons learnt HPV is the second most common STI worldwide
VIN is an important differential for persistent GUD/ Genital warts
Diagnosis often delayed resulting in need for radical surgical intervention
Due to success of ART HPV related disease presenting in patients with suppressed VL and higher CD4 counts
Recommendations
Examine all patients with STI symptoms
Biopsy if lesions atypical or no response to standard Rx, persists> 1 month

18. Scope of the problem 2013 Zimbabwe National Cancer Registry
30.7% Cervical cancer, 1.4% Vulvar cancer, 0.5% Anal cancer1
Incidence of vulvar cancer in Africa by cancer registry2
Malawi: 1.0/100 person years
South Africa: 0.3/100 person years
Uganda: 0.6/100 person year
Incidence of VIN in PLWH not extensively studied
US: VIN incidence 4.67/100 person years HIV infected (1.31 HIV neg)3
1.Zimbabwe National Cancer Registry 2013
2. Forman et al.IARC 2013
3. Massad et al:Am J Obstet Gynaecol 2004

19. Vulvar Intraepithelial Neoplasia
VIN is a premalignant condition of the vulva
2004 classification1
Usual type – HPV asstd lesions (VIN2/VIN3)
Differentiated type – asstd with vulval dermatoses
Usual divided into subtypes according to morphological/histological features
warty, basaloid, mixed
Most common HPV: 16, 18, 31, 33,452
ISSVD 2004
Simbiri et al. Infect Agent Canc 2014

20. Usual type VIN: risk factors
More common pre-menopausal women
ZNCR 68% women <50 yrs at diagnosis1
Immunosuppression
Smoking
High risk HPV
CIN3: 7% patients have concurrent VIN2
Zimbabwe National Cancer Registry 2013
Hording et al. Gynaecol oncol 1995

21. VIN: Presentation Diagnosis: Visual inspection and Biopsy
Asymptomatic (50%)
Vulval pruritus, pain
Dysuria – periurethral VIN
Verrucous, raised, hypopigmented, ulceration
Usually multifocal
Inter labial grooves, posterior forchette, perineum
Diagnosis: Visual inspection and Biopsy

22. VIN: Management
Goal of therapy: prevent progression to squamous cell carcinoma
Treatment options:
Surgical excision: preferred option in HIV infected and high risk
Laser ablation
Imiquimod1
5 Fluorouracil, cidofovir creams
20% recurrence rate regardless of treatment modality
Higher recurrence rates in HIV-infected2
ART decreases the incidence and recurrence of VIN3
1 Van seters M. NEJM 2008
2. Aynaud O Eur J Dermatol 2008
3. Massad et al. Am J Obstet Gynaecol 2004

23. HPV Prevention HPV vaccination Cervarix (16,18) Gardasil (6,11,16,18)
Condom use reduces rates of HPV infection
Screening: secondary prevention of HPV related disease
Annual screening for cervical cancer recommended for PLWH – should include complete genital exam including vulva and perianal region

24. in HIV negative individuals
HPV Vaccination
HPV vaccination is safe, immunogenic and highly efficacious in preventing anogenital HPV related malignancy1,2,3
in HIV negative individuals
Clark LR 2013 J Adolesc Health
Palefsky JM, NEJM 2011
NEJM 2007

25. HPV vaccination in PLWH
HPV vaccines safe and immunogenic in HIV infected population1,2,3
Children from ages 9-18, Women years, Men years
HPV vaccination elicits an antibody response in>95% HIV +ve men2
No relationship between antibody response rates and CD4 counts (if>200)
Antibody response rate higher on ART
HPV vaccination in HIV-infected women3
Lower sero-conversion rates if CD4<200 cells/mm3 VL>10,000copies/ml
Lower antibody titres if CD4<200 cells/mm3
No efficacy data in HIV infected
1.DuVuyst et al J Acquir Immune Defic Syndr
2, Wilkin T et al J Infect Dis
3. Kojic Emet al Clin Infect Dis

26. HPV vaccination in PLWH
High burden of HPV disease despite ART
Continued acquisition of HPV
Sero+ for all vaccines strains uncommon
Boost natural immunity
Safe,immunogenic possible therapeutic role
High rate of HPV infection in HIV may limit vaccine efficacy
Uncertain duration of vaccine induced protection

27. HPV vaccination: Guidelines
WHO recommended primary target group: females 9-13 yrs
2 dose schedule, 6 monthly interval
2015 US Advisory Committee on Immunization Practices(ACIP)  
Women <26 yrs, men <21yrs, MSM <26 yrs 
Immunocompromised  persons <26yrs
2015 Joint Committee on Vaccination and Immunisation   (JCVI)
MSM aged up to 40yrs attending sexual health services
2015 BHIVA as above and including
HIV infected women up to 40 yrs
If ART naïve and CD4< 200 defer until ART established

28. HPV vaccination in PLWH
Vaccination schedule : 3 dose schedule (0, 1-2,6)
Vaccination reactions more common in HIV-infected1
Pain, swelling, erythema (33% vs 9%)
Fever, nausea, vomiting headache (14% vs 2%)
No adverse impact on CD4/viral load
1. Macartney K. Drug saf 2013

29. Summary High burden of HPV associated disease in PLWH
Consider VIN in persistent, atypical GUD/genital warts
Timely diagnosis and effective management of HPV associated disease is essential to prevent progression and avoid need for disfiguring surgical treatment
HPV vaccine safe and immunogenic in PLWH
HPV associated malignancies are vaccine preventable