Nine-valent HPV Vaccine to Prevent Persistent Oral HPV Infection in Men Living With HIV

H. Lee Moffitt Cancer Center and Research Institute, University of Sao Paulo, University of Puerto Rico, Mexican National Institute of Public Health, National Cancer Institute (NCI), Merck Sharp & Dohme LLC

This is a randomized, double-blinded, placebo-controlled Phase III interventional trial of the nine-valent HPV vaccine (9vHPV) to prevent persistent oral HPV infection in adult cisgender men and transgender women living with HIV.

Cisgender men and transgender women ages 20-50 years living with HIV will be enrolled at affiliated clinical sites of the University of Puerto Rico, the National Institute of Public Health, Mexico, and University of São Paulo, Brazil. Participants will have a baseline blood draw for serum HPV antibodies and stored plasma, an oral rinse for HPV testing, stored anal and genital samples for HPV testing as well as a baseline questionnaire about risk factors for oral HPV infection and oropharyngeal cancer. Five-hundred participants will be randomized in a 1:1 allocation to receive 9vHPV or placebo at Day 1, Month 2 and Month 6. Randomization will be stratified based on clinical site (Brazil, Mexico, Puerto Rico) and age (20-30, 31-40, 41-50 years). The age range of enrolled participants will be monitored to ensure enrollment of an approximately even distribution of participants across the age range. 700 participants will be enrolled Follow-up testing for oral HPV will be conducted at Months 2, 6, 7, 12 and every 6 months thereafter up to 42 months post-vaccination. The rationale for oral testing at Months 2 and 6 is to identify participants who are oral HPV positive prior to receiving the full 3 doses of vaccine. In addition, collection of anal canal and genital specimens (penile head, shaft, scrotum) will occur at Day 1, Months 7, 12 and every 6 months thereafter up to 60 months post-randomization. These specimens will be stored for future studies of HIV and HPV and as such will not be analyzed as part of this study. Blood will be stored for serum HPV antibody testing at month 7, 12 and every 12 months thereafter. Participants will undergo a follow-up questionnaire on risk factors for oral HPV and oropharyngeal cancer. Participants will be assessed for adverse events at each follow-up visit. This is a 5 year study. Participants who received placebo will be offered 9vHPV vaccine at the end of the study free of charge. The trial analyses will be case driven with case counting commencing at Month 7, one month post-dose 3. The primary analysis will take place when at least 14 cases of the primary endpoint (incident persistent oral HPV infection with HPV types 6, 11, 16, 18, 31, 33, 45, 52, or 58) have been observed.

Number of participants with new persistent oral HPV infections with one or more of the following types: 6, 11, 16, 18, 31, 33, 45, 52, or 58

The primary endpoint is incident persistent oral HPV infection with HPV types 6, 11, 16, 18, 31, 33, 45, 52, or 58 occurring among participants who remain oral HPV negative to the relevant HPV type through the vaccination period (Day 1-Month 6). Newly acquired oral HPV infections that persist for two or more consecutive oral HPV assessments at least 16 weeks apart with the same 9vHPV detected are defined as "persistent". Case counting will commence with the Month 7 clinical visit and may occur at any timepoint through the final visit, which may be as along as Month 42 for some participants.

Immunogenicity of 9-valent HPV vaccine as measured by proportion of participants experiencing seroconversion for vaccine type.

To evaluate our secondary immunogenicity endpoint, we will assess the proportion of men who seroconvert to the HPV vaccine types 6, 11, 16, 18, 31, 33, 45, 52, or 58 (both in grouped and type-specific analyses) in serum one month post-dose three (Month 7) using the Wilson's method. Men who enter the study seronegative for a particular HPV vaccine type will be monitored for seroconversion following three doses of 9vHPV.

Safety and tolerability of 9-valent HPV vaccine as measured by proportion of participants with >= grade 3 adverse events related to study vaccination or Grade 1 or 2 events leading to premature discontinuation of vaccination, or serious adverse events.

To evaluate the secondary safety and tolerability endpoint, we will report the proportion of participants experiencing a grade 3 or 4 adverse event at least possibly related to study vaccine, grade 1 or 2 adverse events leading to premature discontinuation of vaccine or placebo, and serious adverse events.

Inclusion Criteria: HIV-1 infection Receipt of antiretroviral therapy for at least 6 months Sexually active in the past 6 months; sexual activity is defined as insertive penile-vaginal sex, receptive or insertive penile-anal sex, oral-anal sex, or oral-genital sex Willingness to comply with three-dose vaccine schedule and subsequent six-month visits for up to four years after randomization. Exclusion Criteria: Have a history of oropharyngeal cancer (OPC) or other HPV-related cancer or have suspected OPC or other HPV-related cancer; Have received any doses of a licensed or experimental HPV vaccine or have participated in an HPV vaccine study, Have a history of anaphylaxis to vaccines or are allergic to any vaccine component (e.g.aluminum, yeast, benzonase); Have received any blood products within six months of enrollment, or are currently taking immune-suppressants. Currently have warts/lesions in the oral cavity. Plan to relocate during the study period. Have AIDS-defining condition within 6 months prior to study entry.

Beginning 3 months following publication and available through period of funding of ULACNet (U54 CA242639).

Researchers who provide a methodologically sound proposal for use of the data that is approved by the study investigators and the sponsor. The research must be broadly consistent with that of ULACNet. Researchers may submit a request to the study principal investigator (Timothy Wilkin tiw2001@med.cornell.edu) to request details of request format.