Natural History of Genital Warts: Analysis of the Placebo Arm of 2 Randomized Phase III Trials of a Quadrivalent Human Papillomavirus (Types 6, 11, 16, and 18) Vaccine

TLDR

The placebo arm of two large randomized trials of a quadrivalent HPV vaccine, involving 8,800 women followed for about four years, provides a basis for understanding the natural history of genital warts. The study aimed to delineate the natural history of genital warts in the absence of vaccination. Participants underwent comprehensive perianal, vulvar, and vaginal examinations with biopsies that were blindly reviewed by up to four pathologists and PCR‑tested for 14 HPV genotypes, and were followed for an average of 3.6 years. Among the 8,800 women, 3.4% developed HPV‑6 or HPV‑11 related genital warts (298 cases, 520 lesions), with 90.8% of lesions HPV‑DNA positive, 86% of which were HPV‑6/11, and 31% contained high‑risk HPV types; baseline infection, new or multiple sex partners, and baseline high‑risk HPV DNA were key risk factors, underscoring the pivotal role of HPV‑6 and HPV‑11 and the potential for a vaccine to reduce disease burden.

Abstract

The placebo arm of human papillomavirus (HPV) vaccine trials helps define the natural history of genital warts (GW).Women enrolled in the placebo arm (n = 8800) of 2 randomized trials of a quadrivalent vaccine were examined for the presence of GW for up to 9 visits over approximately 4 years. A comprehensive examination of the perianal area, vulva, and vagina prompted biopsy. Biopsy samples were analyzed by a blinded panel of up to 4 histopathologists and tested for 14 HPV genotypes (6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59) by use of a polymerase chain reaction-based assay. Risk factors for the development of GW were assessed.Women were followed up for an average of 3.6 years (range, 0-4.9 years). Overall, 298 (3.4%) of 8800 participants developed GW related to HPV-6 or HPV-11 (incidence rate, 0.87 cases per 100 person-years-at-risk). In total, 520 distinct lesions were diagnosed as GW. HPV DNA was detected in 472 (90.8%) lesions, with HPV-6 and HPV-11 detected in 447 (86.0%) of these lesions (94.7% of 472 HPV DNA-positive lesions). We found high-risk HPV types in 161 (31.0%) of 520 lesions. Risk factors for HPV-6- and HPV-11-related GW included infection at baseline, acquisition of new sex partners, a higher number of sex partners, and DNA positivity at baseline for a high-risk HPV type.We confirm the major role played by HPV-6 and HPV-11 in GW, as well as associated risk factors. A vaccine that includes these types of HPV could substantially reduce the overall burden of HPV disease.