Amha Tadesse

Four year efficacy of prophylactic human papillomavirus quadrivalent vaccine against low grade cervical, vulvar, and vaginal intraepithelial neoplasia and anogenital warts: randomised controlled trial.

Objectives To evaluate the prophylactic efficacy of the human papillomavirus (HPV) quadrivalent vaccine in preventing low grade cervical, vulvar, and vaginal intraepithelial neoplasias and anogenital warts (condyloma acuminata). Design Data from two international, double blind, placebo controlled, randomised efficacy trials of quadrivalent HPV vaccine (protocol 013 (FUTURE I) and protocol 015 (FUTURE II)). The trials were to be 4 years in length, and the results reported are from final study data of 42 months’ follow-up. Setting Primary care centres and university or hospital associated health centres in 24 countries and territories around the world. Participants 17 622 women aged 16-26 years enrolled between December 2001 and May 2003. Major exclusion criteria were lifetime number of sexual partners (>4), history of abnormal cervical smear test results, and pregnancy. Intervention Three doses of quadrivalent HPV vaccine (for serotypes 6, 11, 16, and 18) or placebo at day 1, month 2, and month 6. Main outcome measures Vaccine efficacy against cervical, vulvar, and vaginal intraepithelial neoplasia grade I and condyloma in a per protocol susceptible population that included subjects who received all three vaccine doses, tested negative for the relevant vaccine HPV types at day 1 and remained negative through month 7, and had no major protocol violations. Intention to treat, generally HPV naive, and unrestricted susceptible populations were also studied. Results In the per protocol susceptible population, vaccine efficacy against lesions related to the HPV types in the vaccine was 96% for cervical intraepithelial neoplasia grade I (95% confidence interval 91% to 98%), 100% for both vulvar and vaginal intraepithelial neoplasia grade I (95% CIs 74% to 100%, 64% to 100% respectively), and 99% for condyloma (96% to 100%). Vaccine efficacy against any lesion (regardless of HPV type) in the generally naive population was 30% (17% to 41%), 75% (22% to 94%), and 48% (10% to 71%) for cervical, vulvar, and vaginal intraepithelial neoplasia grade I, respectively, and 83% (74% to 89%) for condyloma. Conclusions Quadrivalent HPV vaccine provided sustained protection against low grade lesions attributable to vaccine HPV types (6, 11, 16, and 18) and a substantial reduction in the burden of these diseases through 42 months of follow-up. Trial registrations NCT00092521 and NCT00092534.

A Pooled Analysis of Continued Prophylactic Efficacy of Quadrivalent Human Papillomavirus (Types 6/11/16/18) Vaccine against High-grade Cervical and External Genital Lesions

Quadrivalent human papillomavirus (HPV) vaccine has been shown to provide protection from HPV 6/11/16/18–related cervical, vaginal, and vulvar disease through 3 years. We provide an update on the efficacy of the quadrivalent HPV vaccine against high-grade cervical, vaginal, and vulvar lesions based on end-of-study data from three clinical trials. Additionally, we stratify vaccine efficacy by several baseline characteristics, including age, smoking status, and Papanicolaou (Pap) test results. A total of 18,174 females ages 16 to 26 years were randomized and allocated into one of three clinical trials (protocols 007, 013, and 015). Vaccine or placebo was given at baseline, month 2, and month 6. Pap testing was conducted at regular intervals. Cervical and anogenital swabs were collected for HPV DNA testing. Examination for the presence of vulvar and vaginal lesions was also done. Endpoints included high-grade cervical, vulvar, or vaginal lesions (CIN 2/3, VIN 2/3, or VaIN 2/3). Mean follow-up time was 42 months post dose 1. Vaccine efficacy against HPV 6/11/16/18–related high-grade cervical lesions in the per-protocol and intention-to-treat populations was 98.2% [95% confidence interval (95% CI), 93.3-99.8] and 51.5% (95% CI, 40.6-60.6), respectively. Vaccine efficacy against HPV 6/11/16/18–related high-grade vulvar and vaginal lesions in the per-protocol and intention-to-treat populations was 100.0% (95% CI, 82.6-100.0) and 79.0% (95% CI, 56.4-91.0), respectively. Efficacy in the intention-to-treat population tended to be lower in older women, women with more partners, and women with abnormal Pap test results. The efficacy of quadrivalent HPV vaccine against high-grade cervical and external anogenital neoplasia remains high through 42 months post vaccination.

HPV antibody levels and clinical efficacy following administration of a prophylactic quadrivalent HPV vaccine

The efficacy of the quadrivalent Human Papillomavirus (HPV) vaccine is thought to be mediated by humoral immunity. We evaluated the correlation between quadrivalent HPV vaccine-induced serum anti-HPV responses and efficacy. 17,622 women were vaccinated at day 1, and months 2 and 6. At day 1 and at 6-12 months intervals for up to 48 months, subjects underwent Papanicolaou and genital HPV testing. No immune correlate of protection could be found due to low number of cases. Although 40% of vaccine subjects were anti-HPV 18 seronegative at end-of-study, efficacy against HPV 18-related disease remained high (98.4%; 95% CI: 90.5-100.0) despite high attack rates in the placebo group. These results suggest vaccine-induced protection via immune memory, or lower than detectable HPV 18 antibody titers.

Evaluation of quadrivalent HPV 6/11/16/18 vaccine efficacy against cervical and anogenital disease in subjects with serological evidence of prior vaccine type HPV infection

Objective In the quadrivalent (types 6/11/16/18) HPV vaccine (GARDASIL®/SILGARD®) clinical program, 73% of women aged 16-26 were naïve to all vaccine HPV types. In these women, prophylactic administration of the vaccine was highly effective in preventing HPV 6/11/16/18-related cervical disease. Of the remaining women, 15% of had evidence of past infection with one or more vaccine HPV types (seropositive and DNA negative) at the time of enrollment. Here we present an analysis in this group of women to determine the efficacy of the HPV 6/11/16/18 vaccine against new cervical and external anogenital disease related to the same vaccine HPV type which had previously been cleared. Vaccine tolerability in this previously infected population was also assessed. Methods 18,174 women were enrolled into 3 clinical studies. The data presented comprise a subset of these subjects (n = 2,617) who were HPV seropositive and DNA negative at enrollment (for ≥1 vaccine type). In each study, subjects were randomized in a 1:1 ratio to receive HPV 6/11/16/18 vaccine or placebo at day 1, month 2 and month 6 (without knowledge of baseline HPV status). Procedures performed for efficacy data evaluation included detailed genital examination, Pap testing, and collection of cervicovaginal and external genital specimens. Analyses of efficacy were carried out in a population stratified by HPV serology and HPV DNA status at enrollment. Results Subjects were followed for an average of 40 months. Seven subjects in the placebo group developed cervical disease, and eight subjects developed external genital disease related to a vaccine HPV type they had previously encountered. No subject receiving HPV 6/11/16/18 vaccine developed disease to a vaccine HPV type to which they were seropositive and DNA negative at enrolment. Conclusions These results suggest that natural HPV infection-elicited antibodies may not provide complete protection over time, however the immune response to the HPV 6/11/16/18 vaccine appears to prevent reinfection or reactivation of disease with vaccine HPV types. Vaccine-related adverse experiences were higher among subjects receiving vaccine, mostly due to increased injection site adverse experiences.

Combined oral contraceptive use increases HPV persistence but not new HPV detection in a cohort of women from Thailand.

BACKGROUND Women diagnosed with cervical cancer report longer duration and more recent use of combined oral contraceptives (COCs). It is unclear how COC use impacts risk of cervical carcinogenesis. METHODS We estimated the risk of new human papillomavirus (HPV) DNA detection and persistence among 1135 human immunodeficiency virus (HIV)-negative women aged 20-37 years from Thailand who were followed for 18 months at 6-month intervals. Type-specific HPV DNA, demographic information, hormonal contraceptive use, sexual behavior, genital tract coinfection, and Papanicolaou test results were assessed at baseline and each follow-up. RESULTS Women who reported current COC use during follow-up were less likely to clear HPV infection compared with nonusers, independent of sexual behavior, and Papanicolaou test diagnosis (AHR: 0.67 [95% CI: .49-.93]). Similar associations were not observed among women reporting current use of depomedroxyprogesterone acetate (DMPA). Neither COC nor DMPA use was significantly associated with new HPV DNA detection. CONCLUSIONS These data do not support the hypothesis that contraceptive use is associated with cervical cancer risk via increased risk of HPV acquisition. The increased risk of HPV persistence observed among current COC users suggests a possible influence of female sex hormones on host response to HPV infection.

The association of hormonal contraceptive use and HPV prevalence.

Women diagnosed with cervical cancer report longer duration and more recent use of combined oral contraceptives (COCs). It is unclear whether COC use is associated with upstream events of human papillomavirus (HPV) infection prior to development of clinical disease. The objective of our study was to assess the association of contraceptive use on the risk for prevalent HPV infection in a cohort of long‐term hormonal contraceptive (HC) users. One thousand and seventy (n = 1,070) HIV‐negative women aged 20–37 from Thailand enrolled in a prospective study of the natural history of HPV. Baseline HPV genotype information, recency and duration of HC use, sexual behavior, other sexually transmitted infection (STI) information and cervical cytology and histology were assessed. At enrollment, 19.8% and 11.5% of women were infected with any HPV or any high‐risk (HR)‐HPV, respectively. After adjustment for age, current and past sexual risk behaviors, STI history and cytology, the use of COCs for >6 years was found to be associated with an increased risk of infection with any HPV [prevalence ratio (PR): 1.88 (1.21, 2.90)] and any HR‐HPV [PR: 2.68 (1.47, 4.88)] as compared to never users. Recent, long‐term COC use was associated with an increased risk for prevalent HPV infection independent of sexual behavior and cervical abnormalities. No similar association was observed for recent or long duration use of progestin‐only contraceptives (i.e., depomedroxyprogesterone acetate). These data suggest that COC use may impact early upstream events in the natural history of HPV infection.

Prevalence and correlates of HPV among women attending family-planning clinics in Thailand

BackgroundCervical cancer is the most common cancer among women of reproductive age in Thailand. However, information on the prevalence and correlates of anogenital HPV infection in Thailand is sparse.MethodsHPV genotype information, reproductive factors, sexual behavior, other STI and clinical information, and cervical cytology and histology were assessed at enrollment among one thousand two hundred and fifty-six (n = 1,256) HIV negative women aged 20–37 from Thailand enrolled in a prospective study of the natural history of HPV. The type-specific prevalence of HPV was estimated using cervical swab specimens from healthy women and women with a diagnosis of CIN 2/3 at baseline. Prevalence ratios (95% CI) were estimated using Poisson regression to quantify the association of demographic, behavioral, and clinical correlates with prevalent HPV infection.ResultsOverall, 307 (24.6%) and 175 (14.0%) of women were positive for any HPV type and any HR-HPV type, respectively; the most common types were 72, 52, 62, and 16. Among women diagnosed with CIN 2/3 at enrollment (n = 11), the most prevalent HPV types were 52 and 16. In multivariate analysis, HPV prevalence at enrollment was higher among women with: long-term combined oral contraceptive use, a higher number of lifetime sexual partners, a prior Chlamydia infection, and a current diagnosis of Bacterial Vaginosis.ConclusionThe study findings provide important information that can be used in the evaluation of primary and secondary interventions designed to reduce the burden of cervical cancer in Thailand.

Confirmation and quantitation of human papillomavirus type 52 by Roche Linear Array using HPV52-specific TaqMan E6/E7 quantitative real-time PCR.

Human papillomavirus type 52 is highly prevalent in Asia and Africa and accounts for 2-3% of total cervical cancer burden worldwide. The Roche Molecular Systems HPV Linear Array (RMS-LA uses multiple type (i.e. mixed) probes to detect DNA from HPV 52 infection which limits the assays ability to determine HPV 52 status in the presence of HPV 33, 35, or 58 infection. This report presents a simple to use and highly reproducible HPV 52 type-specific quantitative real-time PCR (RT-PCR) assay based on Taqman chemistry for detection and quantification of HPV 52 DNA from cervical swab specimens. Mixed probe positive cervical swab specimens collected from rural and urban women in Thailand (n=68) were used to determine assay agreement and differences in HPV 52 DNA viral load across cytological diagnosis. Forty-eight specimens were determined to be HPV 52 positive by RMS-LA with 94% (n=45) confirmed positive by Taqman assay (kappa: 0.86, 95% CI: 0.74, 0.99). Higher median viral load was observed among women with a Pap diagnosis of >=ASCUS vs. normal/inflammation (8510 copies/1000 cell equivalents vs. 279 copies/1000 cell equivalents, p<0.05). Accurate ascertainment of infection status is important in understanding HPV 52s role in the etiology of cervical cancer as well as for the development of type-specific vaccines.

Kinetics of DNA load predict HPV 16 viral clearance

INTRODUCTION While high HPV 16 viral load measured at a single time point is associated with cervical disease outcomes, few studies have assessed changes in HPV 16 viral load on viral clearance. OBJECTIVE To measure the association between changes in HPV 16 viral load and viral clearance in a cohort of Thai women infected with HPV 16. STUDY DESIGN Fifty women (n=50) between the ages of 18-35 years enrolled in a prospective cohort study were followed up every three months for two years. Women positive for HPV 16 DNA by multiplex TaqMan assay at two or more study visits were selected for viral load quantitation using a type-specific TaqMan based real-time PCR assay. The strength of the association of change in viral load between two visits and viral clearance at the subsequent visit was assessed using a GEE model for binary outcomes. RESULTS At study entry, HPV 16 viral load did not vary by infection outcome. A >2 log decline in viral load across two study visits was found to be strongly associated with viral clearance (AOR: 5.5, 95% CI: 1.4-21.3). HPV 16 viral load measured at a single time point was not associated with viral clearance. CONCLUSIONS These results demonstrate that repeated measurement of HPV 16 viral load may be a useful predictor in determining the outcome of early endpoints of viral infection.

P1-S5.32 The differential associations of HPV prevalence with other sexually transmitted infections in hormonal and non-hormonal contraceptive users

Background This study evaluated the associations of recent sexually transmitted infections (STIs) with cervical HPV prevalence among hormonal and non-hormonal contraceptive users. Methods Data came from a prospective study conducted in 1046 women aged 20–38 years with normal cervical cytology in Thailand. We assessed whether baseline HPV prevalence was predicted by STIs which were newly detected and laboratory-confirmed within 2 years prior to enrolment. Prevalence ratios (PRs) with 95% CIs were estimated using generalised linear models. Results Baseline prevalence of any HPV and high-risk (HR)-HPV were 19.9% and 8.7% respectively. Having genital chlamydia (CT) or gonorrhoea (NG) in the past 2 years was associated with increased risk of any HPV as well as HR-HPV infection after controlling for current and past sexual behaviours, age, contraceptive use and other concurrent STIs [adjusted PRs (aPRs) for any HPV: CT: 1.7 (95% CI 1.1 to 2.7), NG: 1.8 (95% CI 1.1 to 3.1); aPRs for HR-HPV: CT: 2.9 (95% CI 1.3 to 6.5); NG: 3.4 (95% CI 1.7 to 6.7)]. Association between CT and prevalent HR-HPV was statistically significant only among non-hormonal contraceptive users [aPR: 2.7 (95% CI 1.2 to 6.3)] but not among those using hormonal contraceptives in the past 2 years [aPR: combined oral contraceptive (COC) users: 1.1 (95% CI 0.5 to 2.4); users of depot medroxyprogesterone acetate (DMPA): 1.1 (95% CI 0.4 to 3.3)] (Abstract P1-S5.32 table 1). Association of NG with prevalent HR-HPV was observed among those who used COC [aPR: 6.2 (95% CI 2.2 to 17.7)] or DMPA [aPR: 3.5 (95% CI 1.1 to 10.9)] during the past 2 years but not among non-hormonal contraceptive users [aPR: 1.9 (95% CI 0.3 to 10.3)] (Abstract P1-S5.32 table 1). No significant association was found between other STIs and baseline prevalence of HR-HPV in this cohort. Abstract P1-S5.32 Table 1 Association between recent genital infections and prevalent detection of high-risk HPV (N=1046) Total study population a Study population stratified by use of contraceptives in the past 2 years* Detection of any HR-HPV Detection of any HR-HPV Non-hormonal contraceptive users (n=339) COC users (n= 294) DMPA users (n= 413) N = 1046, N (col %) HR-HPV+ n=91 (8.7%), n (row %) PR (95% CI) aPR‡ (95% CI) PR (95% CI) aPR§ (95% CI) PR (95% CI) aPR§ (95% CI) PR (95% CI) aPR§ (95% CI) Detection of the following in the past 2 years† Genital chlamydia  No 925 (88.4) 72 (7.8) 1 1 1 1 1 1 1 1  Yes 121 (11.6) 19 (15.7) 2.02 (1.26 to 3.22) 2.93 (1.33 to 6.47) 3.73 (1.69 to 8.26) 2.74 (1.18 to 6.34) 1.70 (0.84 to 3.47) 1.14 (0.54 to 2.39) 1.22 (0.44 to 3.35) 1.08 (0.35 to 3.28) Genital gonorrhea  No 1020 (97.5) 84 (8.2) 1 1 1 1 1 1 1 1  Yes 26 (2.5) 7 (26.9) 3.27 (1.68 to 6.36) 3.40 (1.73 to 6.65) 2.31 (0.37 to 14.46) 1.87 (0.34 to 10.29) 4.24 (1.79 to 10.03) 6.22 (2.18 to 17.73) 3.29 (1.13 to 9.60) 3.51 (1.13 to 10.93) Bacterial vaginosis  No 875 (83.7) 74 (8.5) 1 1 1 1 1 1 1 1  Yes 171 (16.4) 17 (9.9) 1.18 (0.71 to 1.94) 1.05 (0.63 to 1.75) 1.03 (0.40 to 2.66) 0.75 (0.31 to 1.82) 1.04 (0.46 to 2.36) 0.90 (0.40 to 2.03) 1.57 (0.66 to 3.68) 1.46 (0.57 to 3.70) Positive for HSV-2 serology  No 626 (59.9) 47 (7.5) 1 1 1 1 1 1 1 1  Yes 420 (40.2) 44 (10.5) 1.40 (0.94 to 2.07) 1.26 (0.83 to 1.91) 1.99 (0.90 to 4.38) 1.75 (0.78 to 3.90) 1.53 (0.84 to 2.80) 1.67 (0.89 to 3.15) 0.88 (0.41 to 1.88) 0.73 (0.30 to 1.79) The following covariates were not found to be statistically significantly associated with the outcomes (P>0.05) and did not significantly influence the effect size of the primary association of interest (<10%), and hence were not included in the final models: parity, smoking status, as well as other parameters assessed for sexual behavior, including age of sexual debut, having new partner in the past year, number of sex partners in the past year, frequency of sex in last 6 months. HR-HPV: High-risk HPV, defined as HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 (IARC 2007). * Subjects were formerly enrolled in a 2-year study addressing the effects of hormonal contraceptive use on HIV acquisition (HC-HIV). These subjects were required to adhere to the self-selected contraceptive method for at least 1 year of follow-up in that study (Morrisonet al. AIDS. 2010;24:1778–81). These subjects were reconsented at the end of that study for inclusion in the current study. † Genital infections were detected in pelvic exams and confirmed by laboratory assays. ‡ Estimates adjusted for age at baseline of the current study, number of lifetime partners, partners having sex with others in last 6 months, male partner using condom in last 6 months, other concurrent genital infections, types of contraceptive use in the past 2 years. § Estimates adjusted for age at enrollment of the current study, number of lifetime partners, partners having sex with others in last 6 months, male partner using condom in last 6 months, other concurrent genital infections. COC, combined oral contraceptives; DMPA, depot medroxyprogesterone acetate; HSV-2, Herpes simplex virus 2; PR, Prevalence ratio. Conclusions The differential impact of recent hormonal contraceptive use on the associations of CT and NG with HR-HPV prevalence suggests that the observed correlations may be attributed to biologic interactions between the pathologies of HPV and CT or NG, and not merely residual confounding by shared sexual risks.