How time to healthy singleton delivery could affect decision-making during infertility treatment: a Delphi consensus.

RESEARCH QUESTION: How might time to healthy singleton delivery affect decision-making during infertility treatment? DESIGN: This was a Delphi consensus investigating expert opinion that comprised three steps. In Step 1, 12 experts developed statements. In Step 2, 27 experts (including 12 from Step 1) voted (online survey) on their agreement/disagreement with each statement (providing reasons). Consensus was reached if ≥66% of participants agreed/disagreed. Statements not reaching consensus were revised and the process repeated until consensus was achieved. In Step 3 details of the final agreed statements were communicated. RESULTS: Twelve statements were developed, and consensus (agreement) was reached on all after one round of voting. CONCLUSIONS: Time to healthy singleton delivery should be taken into consideration when making decisions related to infertility treatment, and it is important that fertility treatment is provided in a timely manner, avoiding over- or under-treatment. In all subfertile women <40 years old, IVF outcomes could be optimized by performing up to six single-embryo transfers and certain procedures might reduce time to healthy singleton delivery. These procedures include preimplantation genetic testing for aneuploidies, frozen replacement cycles immediately after failed fresh cycles and use of gonadotrophin-releasing hormone antagonists. Finally, the number of oocytes retrieved should be maximized to increase cumulative live birth rate.

Morphological differences in human zygotes and embryos cultured in different media.

PURPOSE: To compare the effects of four culture media on the quality of human zygotes and embryos. METHODS: Prospective study analyzing 2289 human embryos cultivated simultaneously in two different culture media: HTF, the default medium, with either Universal IVF, Global or IVF-30 as the secondary media. The sibling oocytes by each patient were randomly divided between the two culture media following intracytoplasmic sperm injection (ICSI). On day 1 the pronuclear stage of zygotes were evaluated and on day 2 embryos were evaluated according to the number of cells, percentage of fragmentation and number of nuclei. Z-test and odds ratios were used in the statistical analysis. RESULTS: There was a higher percentage (55.2%) of class A1 + A2 zygotes with IVF-30 compared with HTF, Global or Universal IVF media (49.1%, 44.7% and 44.2%, respectively). The percentage of Top embryos was significantly higher with Global (40.2%) compared with HTF (21.3%), IVF-30 (25.0%) or Universal IVF media (11.2%). CONCLUSIONS: Global medium produced more Top embryos evaluated on day 2 of development.

Inequitable access to assisted reproductive technology for the low-income Brazilian population: a qualitative study.

BACKGROUND: In Brazil, access to infertility care, including assisted reproductive technology (ART) is restricted. This is a second report of a study which evaluated the availability and access of low-income couples to ART services. The objective was to assess the perspective of health professionals and patients with respect to access to ART procedures within the public health network METHODS: Qualitative case studies were conducted in five centres offering ART in the public sector. Semi-structured interviews were conducted with 19 health professionals based at these centres and 48 patients (men and women). Data were analysed using thematic content analysis. RESULTS: All services implemented ART procedures using resources already available. In all except one centre, patients had to pay for the drugs used for the procedures and, in some cases, a fee to cover operative costs and supplies. These charges were incompatible with the financial possibilities of the majority of the low-income Brazilian population. The waiting time for access to ART varied between 3 months and 6 years. In the perspective of both patients and health professionals, the government should help centres to offer ART procedures at no cost to low-income populations. CONCLUSIONS: The low-income Brazilian population has limited access to ART procedures at the public services. The implementation of ART services cannot be based only on initiatives of the professionals involved but must be part of public health policies. One possible solution is to provide ART at lower cost, making it accessible for a large part of the population.

Low priority level for infertility services within the public health sector: a Brazilian case study.

BACKGROUND: In view of the lack of information on availability of public sector infertility services and in order to contribute to the debate on access to these services, we assessed the availability of public sector infertility services, including assisted reproduction technology (ART), in Brazil. MATERIALS AND METHODS: We conducted a cross-sectional study with telephone interviews using a semi-structured questionnaire with Health Secretariats' authorities from the 26 States, the Federal District, 26 Municipal state capitals and another 16 cities with more than 500 000 inhabitants. Also, directors of 26 referral centres and teaching hospitals provide ART procedures supported by the state or university teaching hospitals. RESULTS: Authorities from 24/26 State Secretariats and the Federal District, from 39/42 cities and 26 directors of referral centres and teaching hospitals offering government-funded infertility care and ART were interviewed. In 19/25 states (76%) and 26/39 cities (66.7%), no infertility treatment was available free of charge. The most common reason for lack of services at the state and municipal levels was 'lack of any political decision to implement them', followed by 'lack of human and financial resources'. When ART was available, barriers to access included the fact that patients needed to purchase medication and the more than 1-year waiting list for treatment. CONCLUSIONS: Lack of political commitment results in inequity in the access of low-income couples in Brazil to infertility treatment, including ART.

Use of the levonorgestrel-releasing intrauterine system in women with endometriosis, chronic pelvic pain and dysmenorrhea.

OBJECTIVES: This report is a review of the medical literature on the use of the levonorgestrel-releasing intrauterine system (LNG-IUS) in women with endometriosis, adenomyosis, cyclic pelvic pain and dysmenorrhea. MATERIAL AND METHODS: A review was carried out using the MEDLINE and EMBASE databases to evaluate the use of LNG-IUS in women with endometriosis and adenomyosis. RESULTS: Nine studies were identified, only two of which were randomized clinical trials. One compared the insertion of LNG-IUS after surgery with expectant conduct and the other compared the use of the device with a GnRH analogue (GnRH-a). All studies reported an improvement in pelvic pain and dysmenorrhea, and a reduction in menstrual bleeding. One study found an improvement in the staging of the disease at 6 months of use, and the studies that evaluated the use of LNG-IUS in women with adenomyosis reported a reduction in uterine volume. Furthermore, the only study in which women were followed up for 3 years after insertion found improvement in pelvic pain at 12 months of use. However, there was no improvement after that period. CONCLUSIONS: The use of LNG-IUS is an alternative for the medical treatment of women suffering from endometriosis, adenomyosis, chronic pelvic pain or dysmenorrhea, but experience is limited and long-term studies are necessary to reach definitive conclusions. However, for women who do not wish to become pregnant, this device offers the possibility of at least 5 years of treatment following one single intervention.

Effectiveness of the levonorgestrel-releasing intrauterine system in the treatment of adenomyosis diagnosed and monitored by magnetic resonance imaging.

BACKGROUND: This study was conducted to evaluate the effect of the levonorgestrel-releasing intrauterine system (LNG-IUS) on adenomyotic lesions diagnosed and monitored by magnetic resonance imaging (MRI). STUDY DESIGN: LNG-IUS was inserted during menstrual bleeding in 29 women, 24 to 46 years of age, with MRI-diagnosed adenomyosis associated with menorrhagia and dysmenorrhea. Clinical evaluations were carried out at baseline and at 3 and 6 months postinsertion. MRI was performed at baseline and at 6 months postinsertion and was used to calculate junctional zone thickness (in mm), to define the junctional zone borders, to identify the presence of high-signal foci on T(2)-weighted images and to calculate uterine volume (in mL). RESULTS: A significant reduction of 24.2% in junctional zone thickness was observed (p<.0001); however, no significant decrease in uterine volume was observed (142.6 mL vs. 136.4 mL; p=.2077) between baseline and the 6-month evaluation. A significant decrease in pain score was observed at 3 and 6 months after insertion (p<.0001); however, six women continued to report pain scores >3 at 6 months of observation. At 3 months of use, the most common bleeding pattern was spotting, and at 6 months of observation, oligomenorrhea was the most common pattern observed, although spotting was present in one third of the women. CONCLUSIONS: The insertion of an LNG-IUS led to a reduction in pain and abnormal bleeding associated with adenomyosis. MRI was useful for monitoring response of adenomyotic lesions to the LNG-IUS.

Current practice in the management of symptoms of endometriosis: a survey of Brazilian gynecologists.

OBJECTIVE: The purpose is to assess current medical practice in the diagnosis of endometriosis by Brazilian gynecologists. METHODS: A Cross-sectional study using questionnaires was sent to all gynecologists of the São Paulo State Ob/Gyn Association. RESULTS: A total of 1,660 (31.8%) replies was received. Multiple logistic regression showed that physicians who stated that endometriosis can affect women of all ages was the variable significantly associated with suspicion of endometriosis. Diagnosis was delayed less than 12 months after the first consultation when patients complained of: infertility (OR=1.81, 95% CI 1.01-3.22), dysmenorrhea (OR=2.16, 95% CI 1.18-3.93) or chronic pelvic pain (CPP) (OR=2.17, 95% CI 1.17-4.00). Time until diagnosis was shorter when the complaint was dysmenorrhea (OR=1.33, 95% CI 1.05-1.69) or CPP (OR=1.51, 95% CI 1.19-1.91) and when physicians had participated in congresses and lectures on gynecological endoscopy and endometriosis. CONCLUSION: Gynaecologists who are better informed suspect and diagnose endometriosis at an early stage.

Endometrial histology, microvascular density and caliber, and matrix metalloproteinase-3 in users of the Nestorone-releasing contraceptive implant with and without endometrial breakthrough bleeding.

OBJECTIVE: This descriptive study evaluated endometrial histology, microvascular density and caliber, and quantification of matrix metalloproteinase (MMP-3) expression in long-term users of the Nestorone (NES)-releasing implant who presented or not endometrial breakthrough bleeding (BTB). METHODS: Endometrial biopsies were obtained from 32 healthy women with unpredictable BTB. The quantitative analysis was performed only in 20 samples. RESULTS: The mean duration of use of the implant among the 14 women with BTB was 19.6+/-1.0 months, and the other six women had used the implant for 17.7+/-2.3 months (mean+/-S.E.M.). Histological analysis of the endometrial tissue showed a predominance of progestogenic pattern followed by atrophic and proliferative endometrium in both groups. Mucosal breakdown and glandular pseudostratification were observed in half of the cases. Endometrial vascular density was 73.1+/-10.0 and 57.5+/-24.1 vessels/mm(2), and maximum vessel diameter was 923.3+/-86.0 and 1038.0+/-404 microm (mean+/-S.E.M.) in the group with and without BTB, respectively, without significance, and the rate of cells expressing MMP-3x1000 counted stromal cells was 155.8+/-24.8 and 127.0+/-19.0 (mean+/-S.E.M.) in both groups, respectively, without significance. CONCLUSIONS: This study provides information about some endometrial aspects of women using NES in contraceptive implants. In addition, the endometrium was similar during long-term use of NES-releasing contraceptive implants in women with and without endometrial bleeding.

Enlarged ovarian follicles in users of a levonorgestrel-releasing intrauterine system and contraceptive implant.

OBJECTIVE: To evaluate the prevalence of enlarged ovarian follicles among users of a 20 micrograms/d levonorgestrel-releasing intrauterine system (Mirena, Leiras Oy, Turku, Finland), of subdermal contraceptive implants releasing Nestorone (Population Council, New York, New York) and of the TCu 380A intrauterine device. STUDY DESIGN: A cohort study was conducted at the Universidade Estadual de Campinas, Brazil. Three hundred women were enrolled, with 100 participants in each group. Bimanual pelvic examination and vaginal ultrasound were performed during routine gynecologic examinations in women without complaints. In women with enlarged ovarian follicles (> or = 25 mm), estradiol and progesterone levels were assessed weekly until disappearance or reduction of the ovarian image. RESULTS: Enlarged ovarian follicles were detected in 19%, 10% and 5% of users of the levonorgestrel system, implants and intrauterine device, respectively. Most of the enlarged ovarian images disappeared after 2 weeks of follow-up. Progesterone levels showed that the intrauterine system and TCu 380A IUD (FEI, North Tonawanda, New York) users had presumably ovulated before the first ultrasound examination in contrast to the implant users. CONCLUSION: Physicians and users should be aware that findings of enlarged ovarian follicles during the use of progestin-only contraceptives are transient and that no medical interventions are necessary.

Menstrual bleeding: perspective of Brazilian women.

BACKGROUND: Menstrual patterns, induced amenorrhea and the use of some contraceptive methods which induce non-bleeding are issues under debate among health professionals and women. The objective of the study was to describe perspectives and attitudes of Brazilian women regarding menstruation and its interference in daily activities. STUDY DESIGN: A semistructured questionnaire was applied to nonpregnant, nonlactating women between 18 and 45 years old, who were menstruating, consulting at public health services for other complaints than gynecological or reproductive health care, and staff members and teachers of public universities in one city of each geographic region of Brazil and the Federal District. RESULTS: Of the 885 women interviewed, 51.5% were aged 20-29 years, almost 60% reported normal frequency of bleeding, 22% and 43% reported interference of menstruation in their school activities and in the relationship with their partner, respectively. The value attributed to each interference (<5; ≥ 5; in a scale up to 10) was >5 for more than 60% of the women in all evaluated domains. The most common reason for disliking menstruation was inconvenient and/or discomfort, and for liking menstruation were feeling healthy and confirmation of not being pregnant. The variables associated to liking menstruation were attending <8 years of school and low economic class, having more than one child and no history of premenstrual tension. CONCLUSION: A great proportion of the interviewed women disliked having menstruation even when they did not present menstrual-related problems. However, some women still preferred monthly menstruation because they felt healthy and it was a free pregnancy test.

Premenstrual syndrome as reported by Brazilian women.

OBJECTIVE: To describe the perspectives and attitudes of Brazilian women toward premenstrual syndrome (PMS). METHODS: An exploratory study was conducted in 6 major cities: 1 in each geographic region of Brazil and 1 in the Federal District. Participants were women aged 18-40years who consulted at public healthcare services or who were members of staff/faculty at university. RESULTS: Of 1053 women, 96.1% had heard of PMS; 65.4% considered that all or almost all women experienced the condition; 87.5% stated that symptoms occurred prior to menstruation; and 60.3% thought that they had PMS at the time of the interview. The emotional and physical symptoms most frequently mentioned were nervousness/anxiety (76.4%); mood swings/crying (55.7%); pain, swelling, and tenderness of the breasts (37.3%); and cramps (45.4%). CONCLUSION: Premenstrual syndrome was reported by a large number of Brazilian women; actions need to be taken to provide more effectively the specific information required by both lay people and healthcare professionals.

Serum levonorgestrel levels and endometrial thickness during extended use of the levonorgestrel-releasing intrauterine system.

BACKGROUND: The levonorgestrel-releasing intrauterine system (LNG-IUS) is a contraceptive method approved for five years of use. However, there is some evidence that its life span may be longer. The aim of the study was to evaluate serum levonorgestrel (LNG) and estradiol (E(2)) levels and endometrial thickness every 6 months from 7 to 8 1/2 years after insertion. STUDY DESIGN: At the end of the approved 5-year life span, no replacement devices were available; therefore, 86 women were allowed to retain the same device for a further 2 years. At the 7-year follow-up visit, the women who consented were again allowed to retain the same device for a further 18 months and were followed-up at six-monthly intervals. At each visit, vaginal sonography was performed to measure endometrial thickness, and a blood sample was taken to measure LNG and E(2). RESULTS: Eighty-four months after insertion, 67 women aged 34.3+/-0.8 years (mean+/-SEM) (range, 25-49 years) returned for follow-up. Mean+/-SEM LNG levels decreased from an initial 253+/-27 pg/mL (range, 86-760) during the first 2 months following insertion to 137+/-12 (range, 23-393) at 84 months and 119+/-9 pg/mL (range, 110-129) at 102 months of use (+/-SEM). At 84 months of use, mean+/-SEM endometrial thickness was 2.8+/-0.1 mm, increasing to 3.8+/-0.5 mm at 102 months of use. The incidence of amenorrhea decreased from 41.8% at 84 months to 31.5% at 102 months of use. No correlation was found between LNG levels and bleeding patterns; however, a weak correlation was found between high body mass index (kg/m(2)), high weight, and low serum LNG levels. E(2) levels were similar to those of the follicular phase of the menstrual cycle of regularly menstruating women. CONCLUSIONS: During extended use of the LNG-IUS, serum LNG levels were nearly half those found in the first 2 months of use (Wilcoxon signed rank test); serum E(2) levels were normal. Despite the very thin endometrium, menstrual bleeding was reinstated in many cases. At the end of its 5-year life span, there is a window for changing the LNG-IUS, and physicians and users should not be concerned about delaying replacement of the device for a short time beyond the approved life span; however, maintaining the same device long after its approved life span cannot be recommended.

Induction of immune memory following administration of a prophylactic quadrivalent human papillomavirus (HPV) types 6/11/16/18 L1 virus-like particle (VLP) vaccine.

BACKGROUND: The duration of protection afforded by vaccines represents a critical test of their utility as public health interventions. Some vaccines induce long-term immunity, while others require booster doses. Vaccines that induce long-term protection are usually characterized by the generation of immune memory. Recent trials of a quadrivalent (types 6, 11, 16, 18) human papillomavirus (HPV) vaccine have demonstrated high efficacy through 5 years of follow-up. We evaluated the extent to which the vaccine is able to generate HPV type-specific immune memory. METHODS: A total of 552, 16-23-year-old women were enrolled in a double-blind, placebo-controlled study. At enrollment, subjects were randomized in a 1:1 ratio to receive three-dose regimens of quadrivalent HPV vaccine or placebo with 3 years' follow-up. A subset of 241 subjects (n=114 in the quadrivalent HPV vaccine group and n=127 in the placebo group) underwent 2 further years of follow-up. All extension subjects received quadrivalent HPV vaccine at month 60 to examine the extent of immune memory in response to the primary vaccination series. RESULTS: Serum anti-HPV levels declined post-vaccination, but reached a plateau at month 24 that remained stable through month 60. Administration of a challenge dose of vaccine induced a classic anamnestic response, with anti-HPV levels 1 week post-challenge reaching levels observed 1 month following the completion of the three-dose primary series. At 1 month post-challenge, anti-HPV responses were higher than those observed 1-month post-dose 3. DISCUSSION: A three-dose regimen of quadrivalent HPV vaccine induces high efficacy and stable anti-HPV levels for at least 5 years. Vaccination also induces robust immune memory. These findings suggest that the efficacy of this vaccine will be long lasting.

Endometrial chemokines, uterine natural killer cells and mast cells in long-term users of the levonorgestrel-releasing intrauterine system.

OBJECTIVE: The objective was to assess endometrial chemokines in users of the levonorgestrel-releasing intrauterine system (LNG-IUS) and correlate them with leucocyte populations, uterine natural killer cells (uNK) and mast cells (MCs). MATERIALS AND METHODS: Endometrium was obtained from two groups of women who had been using LNG-IUS for 3 years or more: 11 amenorrhoeic women formed the non-bleeding group and 15 women who maintained some form of cyclic bleeding comprised the bleeding group. Specific antibodies were used for the assessment of neutrophils, uNK cells and MCs. Immunohistochemistry was performed to locate the chemokines 6Ckine and interleukin-8 (IL-8). RESULTS: Neutrophils were few and without differences between the two groups. uNK cells were significantly higher in the bleeding group (P < 0.0001). There was no difference between the total number of MCs and activated MCs, but there was a greater extracellular area stained for MC tryptase (P < 0.05). Chemokines 6CKine and IL-8 were abundant in the stroma and in the epithelium, and there was no difference between the groups. CONCLUSIONS: We observed more uNK cells in users with bleeding and a greater extracellular area stained for MC tryptase, although there were no differences between the number of MCs and activated MCs or the chemokines 6CKine and IL-8. uNK cells and MC products may play a role in provoking breakthrough bleeding in long-term users of the LNG-IUS.

A cross-sectional study of the forearm bone density of long-term users of levonorgestrel-releasing intrauterine system.

BACKGROUND: There are concerns about the effect of hormonal contraceptives on bone mineral density (BMD), but there is currently no information available on the effect of the levonorgestrel-releasing intrauterine system (LNG-IUS) on BMD. The objective of this study was to compare the BMD of LNG-IUS users with that of controls using the TCu380A intrauterine device (IUD). MATERIALS AND METHODS: A cross-sectional study paired 53 women, aged 25-51 years, who had been using the LNG-IUS for 7 years, with 53 IUD users, according to age (+/-1 year) and body mass index (BMI; kg/m2) (+/-1). BMD was evaluated at the midshaft of the ulna and the distal radius of the nondominant forearm using double X-ray absorptiometry. RESULTS: Mean age of women was 34 years. BMI was slightly over 25 in both groups. Estradiol was normal. Mean BMD was 0.469 +/- 0.008 and 0.467 +/- 0.009 and 0.409 +/- 0.009 and 0.411 +/- 0.009 at the midshaft of the ulna and distal radius in LNG-IUS and IUD users, respectively, without significant differences. CONCLUSIONS: Women aged 25-51 years, using the LNG-IUS for 7 years, had a mean BMD similar to that of the control group of TCu380A IUD users.

A prospective study of the forearm bone density of users of etonorgestrel- and levonorgestrel-releasing contraceptive implants.

BACKGROUND: The aim of the study was to compare bone mineral density (BMD) before insertion and at 18 months of use of etonorgestrel- and levonorgestrel-releasing contraceptive implants. METHODS: One hundred and eleven women, 19-43 years of age, were randomly allocated to two groups: 56 to etonorgestrel and 55 to levonorgestrel. BMD was evaluated at the midshaft of the ulna and at the distal radius of the non-dominant forearm using dual-energy X-ray absorptiometry before insertion and at 18 months of use. RESULTS: There was no difference in baseline demographic or anthropometric characteristics, or in BMD of users of either model of implant. BMD was significantly lower at 18 months of use at the midshaft of the ulna in both groups of users. However, no difference was found at the distal radius. Multiple linear regression analysis showed that the variables associated with BMD at 18 months of use in both implant groups were baseline BMD, body mass index (BMI) and difference in BMI (0 versus 18 months of use). CONCLUSIONS: Women of 19-43 years of age using either one of the implants showed lower BMD at 18 months of use at the midshaft of the ulna, however, without a difference at the distal radius.

Immunologic responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 18.

Human papillomavirus (HPV) infection causes cervical cancer and genital warts. Young women (1106) were randomized to receive one of three formulations of a quadrivalent HPV (Types 6/11/16/18) L1 virus-like particle (VLP) vaccine or one of two placebo formulations. The goal was to assess vaccine safety and immunogenicity in baseline HPV 6/11/16 or 18-naïve and previously infected subjects. All three formulations were highly immunogenic. At Month 2 (postdose 1), among women with vaccine-type antibodies at baseline, vaccine-induced anti-HPV responses were approximately 12- to 26-fold higher than those observed in baseline-naïve women, suggesting an anamnestic response. Following an initial, similar sized decline, anti-HPV responses plateaued and remained stable through end-of-study (3.0 years). No vaccine-related serious adverse experiences were reported.

Randomized clinical trial of a levonorgestrel-releasing intrauterine system and a depot GnRH analogue for the treatment of chronic pelvic pain in women with endometriosis.

BACKGROUND: The objective of this multicentre randomized, controlled clinical trial was to compare the efficacy of a levonorgestrel-releasing intrauterine system (LNG-IUS) and a depot-GnRH-analogue in the control of endometriosis-related pain over a period of six months. METHODS: Eighty-two women, 18 to 40 years of age (mean 30 years), with endometriosis, dysmenorrhoea and/or CPP, were randomized using a computer-generated system of sealed envelopes into either LNG-IUS (n = 39) or GnRH analogue (n = 43) treatment groups at three university centres. Daily scores of endometriosis-associated CPP were evaluated using the Visual Analogue Scale (VAS), daily bleeding score was calculated from bleeding calendars, and improvement in quality of life was evaluated using the Psychological General Well-Being Index Questionnaire (PGWBI). The pain score diary was based on the VAS in which women recorded the occurrence and intensity of pain on a daily basis. A monthly score was calculated from the result of the sum of the daily scores divided by the number of days in each observation period. RESULTS: CPP decreased significantly from the first month throughout the six months of therapy with both forms of treatment and there was no difference between the groups (P > 0.999). In both treatment groups, women with stage III and IV endometriosis showed a more rapid improvement in the VAS pain score than women with stage I and II of the disease (P < 0.002). LNG-IUS users had a higher bleeding score than GnRH-analogue users at all time points of observation with 34% and 71% of patients in the LNG-IUS and GnRH-analogue groups, respectively, reporting no bleeding during the first treatment month, and 70% and 98% reporting no bleeding during the sixth month. No difference was observed between groups with reference to improvement in quality of life. CONCLUSIONS: Both, the LNG-IUS and the GnRH-analogue were effective in the treatment of CPP-associated endometriosis, although no differences were observed between the two treatments. Among the additional advantages of the LNG-IUS is the fact that it does not provoke hypoestrogenism and that it requires only one medical intervention for its introduction every 5 years. This device could therefore become the treatment of choice for CPP-associated endometriosis in women who do not wish to conceive.

Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial.

BACKGROUND: A randomised double-blind placebo-controlled phase II study was done to assess the efficacy of a prophylactic quadrivalent vaccine targeting the human papillomavirus (HPV) types associated with 70% of cervical cancers (types 16 and 18) and with 90% of genital warts (types 6 and 11). METHODS: 277 young women (mean age 20.2 years [SD 1.7]) were randomly assigned to quadrivalent HPV (20 microg type 6, 40 microg type 11, 40 microg type 16, and 20 microg type 18) L1 virus-like-particle (VLP) vaccine and 275 (mean age 20.0 years [1.7]) to one of two placebo preparations at day 1, month 2, and month 6. For 36 months, participants underwent regular gynaecological examinations, cervicovaginal sampling for HPV DNA, testing for serum antibodies to HPV, and Pap testing. The primary endpoint was the combined incidence of infection with HPV 6, 11, 16, or 18, or cervical or external genital disease (ie, persistent HPV infection, HPV detection at the last recorded visit, cervical intraepithelial neoplasia, cervical cancer, or external genital lesions caused by the HPV types in the vaccine). Main analyses were done per protocol. FINDINGS: Combined incidence of persistent infection or disease with HPV 6, 11, 16, or 18 fell by 90% (95% CI 71-97, p<0.0001) in those assigned vaccine compared with those assigned placebo. INTERPRETATION: A vaccine targeting HPV types 6, 11, 16, 18 could substantially reduce the acquisition of infection and clinical disease caused by common HPV types.