Unnop Jaisamrarn

Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women

BACKGROUND The human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine was immunogenic, generally well tolerated, and effective against HPV-16 or HPV-18 infections, and associated precancerous lesions in an event-triggered interim analysis of the phase III randomised, double-blind, controlled PApilloma TRIal against Cancer In young Adults (PATRICIA). We now assess the vaccine efficacy in the final event-driven analysis. METHODS Women (15-25 years) were vaccinated at months 0, 1, and 6. Analyses were done in the according-to-protocol cohort for efficacy (ATP-E; vaccine, n=8093; control, n=8069), total vaccinated cohort (TVC, included all women receiving at least one vaccine dose, regardless of their baseline HPV status; represents the general population, including those who are sexually active; vaccine, n=9319; control, n=9325), and TVC-naive (no evidence of oncogenic HPV infection at baseline; represents women before sexual debut; vaccine, n=5822; control, n=5819). The primary endpoint was to assess vaccine efficacy against cervical intraepithelial neoplasia 2+ (CIN2+) that was associated with HPV-16 or HPV-18 in women who were seronegative at baseline, and DNA negative at baseline and month 6 for the corresponding type (ATP-E). This trial is registered with ClinicalTrials.gov, number NCT00122681. FINDINGS Mean follow-up was 34.9 months (SD 6.4) after the third dose. Vaccine efficacy against CIN2+ associated with HPV-16/18 was 92.9% (96.1% CI 79.9-98.3) in the primary analysis and 98.1% (88.4-100) in an analysis in which probable causality to HPV type was assigned in lesions infected with multiple oncogenic types (ATP-E cohort). Vaccine efficacy against CIN2+ irrespective of HPV DNA in lesions was 30.4% (16.4-42.1) in the TVC and 70.2% (54.7-80.9) in the TVC-naive. Corresponding values against CIN3+ were 33.4% (9.1-51.5) in the TVC and 87.0% (54.9-97.7) in the TVC-naive. Vaccine efficacy against CIN2+ associated with 12 non-vaccine oncogenic types was 54.0% (34.0-68.4; ATP-E). Individual cross-protection against CIN2+ associated with HPV-31, HPV-33, and HPV-45 was seen in the TVC. INTERPRETATION The HPV-16/18 AS04-adjuvanted vaccine showed high efficacy against CIN2+ associated with HPV-16/18 and non-vaccine oncogenic HPV types and substantial overall effect in cohorts that are relevant to universal mass vaccination and catch-up programmes. FUNDING GlaxoSmithKline Biologicals.

Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial

BACKGROUND The aim of this interim analysis of a large, international phase III study was to assess the efficacy of an AS04 adjuvanted L1 virus-like-particle prophylactic candidate vaccine against infection with human papillomavirus (HPV) types 16 and 18 in young women. METHODS 18,644 women aged 15-25 years were randomly assigned to receive either HPV16/18 vaccine (n=9319) or hepatitis A vaccine (n=9325) at 0, 1, and 6 months. Of these women, 88 were excluded because of high-grade cytology and 31 for missing cytology results. Thus, 9258 women received the HPV16/18 vaccine and 9267 received the control vaccine in the total vaccinated cohort for efficacy, which included women who had prevalent oncogenic HPV infections, often with several HPV types, as well as low-grade cytological abnormalities at study entry and who received at least one vaccine dose. We assessed cervical cytology and subsequent biopsy for 14 oncogenic HPV types by PCR. The primary endpoint--vaccine efficacy against cervical intraepithelial neoplasia (CIN) 2+ associated with HPV16 or HPV18--was assessed in women who were seronegative and DNA negative for the corresponding vaccine type at baseline (month 0) and allowed inclusion of lesions with several oncogenic HPV types. This interim event-defined analysis was triggered when at least 23 cases of CIN2+ with HPV16 or HPV18 DNA in the lesion were detected in the total vaccinated cohort for efficacy. Analyses were done on a modified intention-to-treat basis. This trial is registered with the US National Institutes of Health clinical trial registry, number NCT00122681. FINDINGS Mean length of follow-up for women in the primary analysis for efficacy at the time of the interim analysis was 14.8 (SD 4.9) months. Two cases of CIN2+ associated with HPV16 or HPV18 DNA were seen in the HPV16/18 vaccine group; 21 were recorded in the control group. Of the 23 cases, 14 (two in the HPV16/18 vaccine group, 12 in the control group) contained several oncogenic HPV types. Vaccine efficacy against CIN2+ containing HPV16/18 DNA was 90.4% (97.9% CI 53.4-99.3; p<0.0001). No clinically meaningful differences were noted in safety outcomes between the study groups. INTERPRETATION The adjuvanted HPV16/18 vaccine showed prophylactic efficacy against CIN2+ associated with HPV16 or HPV18 and thus could be used for cervical cancer prevention.

Cross-protective efficacy of HPV-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by non-vaccine oncogenic HPV types: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial

BACKGROUND We evaluated the efficacy of the human papillomavirus HPV-16/18 AS04-adjuvanted vaccine against non-vaccine oncogenic HPV types in the end-of-study analysis after 4 years of follow-up in PATRICIA (PApilloma TRIal against Cancer In young Adults). METHODS Healthy women aged 15-25 years with no more than six lifetime sexual partners were included in PATRICIA irrespective of their baseline HPV DNA status, HPV-16 or HPV-18 serostatus, or cytology. Women were randomly assigned (1:1) to HPV-16/18 vaccine or a control hepatitis A vaccine, via an internet-based central randomisation system using a minimisation algorithm to account for age ranges and study sites. The study was double-blind. The primary endpoint of PATRICIA has been reported previously; the present analysis evaluates cross-protective vaccine efficacy against non-vaccine oncogenic HPV types in the end-of-study analysis. Analyses were done for three cohorts: the according-to-protocol cohort for efficacy (ATP-E; vaccine n=8067, control n=8047), total vaccinated HPV-naive cohort (TVC-naive; no evidence of infection with 14 oncogenic HPV types at baseline, approximating young adolescents before sexual debut; vaccine n=5824, control n=5820), and the total vaccinated cohort (TVC; all women who received at least one vaccine dose, approximating catch-up populations that include sexually active women; vaccine n=9319, control=9325). Vaccine efficacy was evaluated against 6-month persistent infection, cervical intraepithelial neoplasia grade 2 or greater (CIN2+) associated with 12 non-vaccine HPV types (individually or as composite endpoints), and CIN3+ associated with the composite of 12 non-vaccine HPV types. This study is registered with ClinicalTrials.gov, number NCT00122681. FINDINGS Consistent vaccine efficacy against persistent infection and CIN2+ (with or without HPV-16/18 co-infection) was seen across cohorts for HPV-33, HPV-31, HPV-45, and HPV-51. In the most conservative analysis of vaccine efficacy against CIN2+, where all cases co-infected with HPV-16/18 were removed, vaccine efficacy was noted for HPV-33 in all cohorts, and for HPV-31 in the ATP-E and TVC-naive. Vaccine efficacy against CIN2+ associated with the composite of 12 non-vaccine HPV types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68), with or without HPV-16/18 co-infection, was 46·8% (95% CI 30·7-59·4) in the ATP-E, 56·2% (37·2-69·9) in the TVC-naive, and 34·2% (20·4-45·8) in the TVC. Corresponding values for CIN3+ were 73·8% (48·3-87·9), 91·4% (65·0-99·0), and 47·5% (22·8-64·8). INTERPRETATION Data from the end-of-study analysis of PATRICIA show cross-protective efficacy of the HPV-16/18 vaccine against four oncogenic non-vaccine HPV types-HPV-33, HPV-31, HPV-45, and HPV-51-in different trial cohorts representing diverse groups of women. FUNDING GlaxoSmithKline Biologicals.

Natural History of Progression of HPV Infection to Cervical Lesion or Clearance: Analysis of the Control Arm of the Large, Randomised PATRICIA Study

Background The control arm of PATRICIA (PApillomaTRIal against Cancer In young Adults, NCT00122681) was used to investigate the risk of progression from cervical HPV infection to cervical intraepithelial neoplasia (CIN) or clearance of infection, and associated determinants. Methods and Findings Women aged 15-25 years were enrolled. A 6-month persistent HPV infection (6MPI) was defined as detection of the same HPV type at two consecutive evaluations over 6 months and clearance as ≥2 type-specific HPV negative samples taken at two consecutive intervals of approximately 6 months following a positive sample. The primary endpoint was CIN grade 2 or greater (CIN2+) associated with the same HPV type as a 6MPI. Secondary endpoints were CIN1+/CIN3+ associated with the same HPV type as a 6MPI; CIN1+/CIN2+/CIN3+ associated with an infection of any duration; and clearance of infection. The analyses included 4825 women with 16,785 infections (3363 womenwith 6902 6MPIs). Risk of developing a CIN1+/CIN2+/CIN3+ associated with same HPV type as a 6MPI varied with HPV type and was significantly higher for oncogenic versus non-oncogenic types. Hazard ratios for development of CIN2+ were 10.44 (95% CI: 6.96-15.65), 9.65 (5.97-15.60), 5.68 (3.50-9.21), 5.38 (2.87-10.06) and 3.87 (2.38-6.30) for HPV-16, HPV-33, HPV-31, HPV-45 and HPV-18, respectively. HPV-16 or HPV-33 6MPIs had ~25-fold higher risk for progression to CIN3+. Previous or concomitant HPV infection or CIN1+ associated with a different HPV type increased risk. Of the different oncogenic HPV types, HPV-16 and HPV-31 infections were least likely to clear. Conclusions Cervical infections with oncogenic HPV types increased the risk of CIN2+ and CIN3+. Previous or concomitant infection or CIN1+ also increased the risk. HPV-16 and HPV-33 have by far the highest risk of progression to CIN3+, and HPV-16 and HPV-31 have the lowest chance of clearance.

Efficacy of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in women aged 15-25 years with and without serological evidence of previous exposure to HPV-16/18

In the Phase III PATRICIA study (NCT00122681), the human papillomavirus (HPV)‐16/18 AS04‐adjuvanted vaccine (Cervarix®, GlaxoSmithKline Biologicals) was highly efficacious against HPV‐16/18 infections and precancerous lesions in women HPV‐16/18 deoxyribose nucleic acid (DNA) negative and seronegative at baseline. We present further data on vaccine efficacy (VE) against HPV‐16/18 in the total vaccinated cohort including women who may have been exposed to HPV‐16/18 infection before vaccination. In women with no evidence of current or previous HPV‐16/18 infection (DNA negative and seronegative), VE was 90.3% (96.1% confidence interval: 87.3–92.6) against 6‐month persistent infection (PI), 91.9% (84.6–96.2) against cervical intraepithelial neoplasia (CIN)1+ and 94.6% (86.3–98.4) against CIN2+ [97.7% (91.1–99.8) when using the HPV type assignment algorithm (TAA)]. In women HPV‐16/18 DNA negative but with serological evidence of previous HPV‐16/18 infection (seropositive), VE was 72.3% (53.0–84.5) against 6‐month PI, 67.2% (10.9–89.9) against CIN1+, and 68.8% (−28.3–95.0) against CIN2+ [88.5% (10.8–99.8) when using TAA]. In women with no evidence of current HPV‐16/18 infection (DNA negative), regardless of their baseline HPV‐16/18 serological status, VE was 88.7% (85.7–91.1) against 6‐month PI, 89.1% (81.6–94.0) against CIN1+ and 92.4% (84.0–97.0) against CIN2+ [97.0% (90.6–99.5) when using TAA]. In women who were DNA positive for one vaccine type, the vaccine was efficacious against the other vaccine type. The vaccine did not impact the outcome of HPV‐16/18 infections present at the time of vaccination. Vaccination was generally well tolerated regardless of the womans HPV‐16/18 DNA or serological status at entry.

Prevalence of osteopenia and osteoporosis in Thai women.

ObjectiveTo determine the age-specific and age-adjusted prevalence of osteopenia and osteoporosis in pre-and postmenopausal Thai women. MethodsThis was a descriptive study of 1,935 Thai women ranging in age from 40 to 80 years, with randomly selected strata using multistage sampling and stratifying from six representative provinces of the country. After recruiting, all the women were interviewed by a well-trained interviewer using structured questionnaires. Bone mineral density (BMD) of lumbar spine 1-4 and nondominant hip was measured by a dual energy photon absorptiometer. The investigators were trained and standardized; inter-and intraobserver variations were measured periodically. Every BMD outcome was re-examined by the specialist. Age-specific prevalence of osteoporosis and osteopenia were determined using both Thai and Western standard BMD values. Age-adjusted prevalence of osteopenia and osteoporosis was calculated using the age-adjusted direct method. ResultsUsing the Thai BMD reference, the age-specific prevalence of osteoporosis among Thai women rose progressively with increasing age to more than 50% after the age of 70. The age-adjusted prevalence of osteoporosis also rose progressively. It was 19.8%, 13.6%, and 10% for lumbar spine, femoral neck, and intertrochanteric. The age-adjusted prevalence of osteoporosis indicates the overall magnitude of that condition in the population or country. In our study, using a Western BMD reference resulted in a misleadingly high prevalence of osteoporosis in the population of Asian countries. ConclusionIt is important to calculate the age-adjusted prevalence of osteopenia and osteoporosis to address the overall magnitude of the problem in Thai women. This will allow us to predict the socioeconomic impact of preventable chronic conditions such as osteoporosis. The results obtained from this study are important data for public health policy: maximizing bone mass throughout life as well as detection of important risk factors is essential.

The Asian Menopause Survey: Knowledge, perceptions, hormone treatment and sexual function

OBJECTIVE To provide current insights into the opinions, attitudes, and knowledge of menopausal women in Asia regarding menopause and hormone replacement therapy (HRT). STUDY DESIGN Cross-sectional. MAIN OUTCOME MEASURES Between January 2006 and February 2006, 1000 postmenopausal women from China, Malaysia, Taiwan, Thailand and Hong Kong were interviewed to determine postmenopausal symptoms, HRT use and knowledge, breast discomfort and knowledge of breast cancer risks, and sexual function. RESULTS Almost all women reported experiencing postmenopausal symptoms. Sleeplessness (42%) was reported as the main reason for seeking treatment. On average, 54% of women were aware of HRT, despite the fact that most (38%) were unable to mention any associated benefits. Most women had used natural or herbal treatments (37%) for the alleviation of menopausal symptoms. Only 19% had received HRT. 27% of respondents reported having breast discomfort, while 70% reported performing self-breast examinations. 53% of women had never received a mammogram, despite breast cancer concern (50%). 24% of women described HRT as being a risk factor for breast cancer. Most women and their partners reported no reductions in sexual function (66 and 51%, respectively), while 90% of respondents did not seek treatment for reduced sexual function. In the event of sexual dysfunction, 33% of women replied that they would be willing to seek treatment. CONCLUSIONS Many Asian women experience postmenopausal symptoms that are often left untreated (due to the acceptance of menopause as a natural process) or treated with herbal/natural remedies. There was a general lack of knowledge among these women regarding treatment options, HRT, and possible risks associated with HRT. A more concerted effort should be made to better disseminate information regarding the pathogenesis and risk factors associated with breast cancer, menopause, and menopausal symptoms to Asian women.

Efficacy of Human Papillomavirus 16 and 18 (HPV-16/18) AS04-Adjuvanted Vaccine against Cervical Infection and Precancer in Young Women: Final Event-Driven Analysis of the Randomized, Double-Blind PATRICIA Trial

ABSTRACT We report final event-driven analysis data on the immunogenicity and efficacy of the human papillomavirus 16 and 18 ((HPV-16/18) AS04-adjuvanted vaccine in young women aged 15 to 25 years from the PApilloma TRIal against Cancer In young Adults (PATRICIA). The total vaccinated cohort (TVC) included all randomized participants who received at least one vaccine dose (vaccine, n = 9,319; control, n = 9,325) at months 0, 1, and/or 6. The TVC-naive (vaccine, n = 5,822; control, n = 5,819) had no evidence of high-risk HPV infection at baseline, approximating adolescent girls targeted by most HPV vaccination programs. Mean follow-up was approximately 39 months after the first vaccine dose in each cohort. At baseline, 26% of women in the TVC had evidence of past and/or current HPV-16/18 infection. HPV-16 and HPV-18 antibody titers postvaccination tended to be higher among 15- to 17-year-olds than among 18- to 25-year-olds. In the TVC, vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 1 or greater (CIN1+), CIN2+, and CIN3+ associated with HPV-16/18 was 55.5% (96.1% confidence interval [CI], 43.2, 65.3), 52.8% (37.5, 64.7), and 33.6% (−1.1, 56.9). VE against CIN1+, CIN2+, and CIN3+ irrespective of HPV DNA was 21.7% (10.7, 31.4), 30.4% (16.4, 42.1), and 33.4% (9.1, 51.5) and was consistently significant only in 15- to 17-year-old women (27.4% [10.8, 40.9], 41.8% [22.3, 56.7], and 55.8% [19.2, 76.9]). In the TVC-naive, VE against CIN1+, CIN2+, and CIN3+ associated with HPV-16/18 was 96.5% (89.0, 99.4), 98.4% (90.4, 100), and 100% (64.7, 100), and irrespective of HPV DNA it was 50.1% (35.9, 61.4), 70.2% (54.7, 80.9), and 87.0% (54.9, 97.7). VE against 12-month persistent infection with HPV-16/18 was 89.9% (84.0, 94.0), and that against HPV-31/33/45/51 was 49.0% (34.7, 60.3). In conclusion, vaccinating adolescents before sexual debut has a substantial impact on the overall incidence of high-grade cervical abnormalities, and catch-up vaccination up to 18 years of age is most likely effective. (This study has been registered at ClinicalTrials.gov under registration no. NCT001226810.)

Prevalence and risk factors for cervical HPV infection and abnormalities in young adult women at enrolment in the multinational PATRICIA trial

OBJECTIVE We evaluated baseline data from the PApilloma TRIal against Cancer In young Adults (PATRICIA; NCT00122681) on the association between behavioral risk factors and HPV infection and cervical abnormalities. METHODS Women completed behavioral questionnaires at baseline. Prevalence of HPV infection and cervical abnormalities (detected by cytological or histological procedures) and association with behavioral risk factors were analyzed by univariate and stepwise multivariable logistic regressions. RESULTS 16782 women completed questionnaires. Among 16748 women with data for HPV infection, 4059 (24.2%) were infected with any HPV type. Among 16757 women with data for cytological abnormalities, 1626 (9.7%) had a cytological abnormality, of whom 1170 (72.0%) were infected with at least one oncogenic HPV type including HPV-16 (22.7%) and HPV-18 (9.3%). Multivariable analysis (adjusted for age and region, N=14404) showed a significant association between infection with any HPV type and not living with a partner, smoking, age <15 years at first sexual intercourse, higher number of sexual partners during the past 12 months, longer duration of hormonal contraception and history of sexually transmitted infection (STI). For cervical abnormalities, only history of STI (excluding Chlamydia trachomatis) remained significant in the multivariable analysis after adjusting for HPV infection. CONCLUSIONS Women reporting 3+ sexual partners in the past 12 months had the highest risk of HPV infection at baseline. HPV infection was the main risk factor for cervical abnormalities, and history of STIs excluding Chlamydia trachomatis increased risk to a lesser extent. Although behavioral factors can influence risk, all sexually active women are susceptible to HPV infection.

Risk of Newly Detected Infections and Cervical Abnormalities in Women Seropositive for Naturally Acquired Human Papillomavirus Type 16/18 Antibodies: Analysis of the Control Arm of PATRICIA

Background. We examined risk of newly detected human papillomavirus (HPV) infection and cervical abnormalities in relation to HPV type 16/18 antibody levels at enrollment in PATRICIA (Papilloma Trial Against Cancer in Young Adults; NCT00122681). Methods. Using Poisson regression, we compared risk of newly detected infection and cervical abnormalities associated with HPV-16/18 between seronegative vs seropositive women (15–25 years) in the control arm (DNA negative at baseline for the corresponding HPV type [HPV-16: n = 8193; HPV-18: n = 8463]). Results. High titers of naturally acquired HPV-16 antibodies and/or linear trend for increasing antibody levels were significantly associated with lower risk of incident and persistent infection, atypical squamous cells of undetermined significance or greater (ASCUS+), and cervical intraepithelial neoplasia grades 1/2 or greater (CIN1+, CIN2+). For HPV-18, although seropositivity was associated with lower risk of ASCUS+ and CIN1+, no association between naturally acquired antibodies and infection was demonstrated. Naturally acquired HPV-16 antibody levels of 371 (95% confidence interval [CI], 242–794), 204 (95% CI, 129–480), and 480 (95% CI, 250–5756) EU/mL were associated with 90% reduction of incident infection, 6-month persistent infection, and ASCUS+, respectively. Conclusions. Naturally acquired antibodies to HPV-16, and to a lesser extent HPV-18, are associated with some reduced risk of subsequent infection and cervical abnormalities associated with the same HPV type.