OBJECTIVE: To identify an appropriate dose for a new contraceptive levonorgestrel intrauterine system (LNG-IUS). DESIGN: Randomized, open-label, three-arm, phase II study. SETTING: Thirty-seven ...centers in five European countries. PATIENT(S): Parous or nulliparous women aged 21–40 years. INTERVENTION(S): Treatment with LNG-IUSs with initial in vitro release rates of 12 or 16 μg/d (LNG-IUS12/16) or 20 μg/d (Mirena). MAIN OUTCOME MEASURE(S): Pearl index, bleeding profile, ease/pain of placement/removal, adverse events. RESULT(S): A total of 738 subjects had an LNG-IUS placed (LNG-IUS12, n = 239; LNG-IUS16, n = 245; Mirena, n = 254). One, 5, and 0 pregnancies occurred in the LNG-IUS12, LNG-IUS16, and Mirena groups, respectively (3-year unadjusted Pearl indices: 0.17, 0.82, and 0). The bleeding profiles were similar in all groups, although total bleeding and spotting days decreased with increasing LNG dose. During 3 years, 10 subjects in the LNG-IUS12 (2 women), LNG-IUS16 (3 women), and Mirena (5 women) groups reported serious adverse events, possibly related to study treatment. Placement of LNG-IUS12 and LNG-IUS16 was considered easy in 94% versus 86.2% in the Mirena group and 72.3% in the LNG-IUS12/LNG-IUS16 group reported either “no pain” or only “mild pain” during placement versus 57.9% in the Mirena group. CONCLUSION(S): LNG-IUS12 and LNG-IUS16 provided effective contraception, acceptable bleeding patterns, and were well tolerated compared with Mirena.
Summary 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.
To assess the pharmacokinetics and pharmacodynamics of levonorgestrel intrauterine system (LNG-IUS) 13.5 mg and LNG-IUS 19.5 mg (total content).
Pooled pharmacokinetic and pharmacodynamic analyses of ...phase II and III studies.
Randomized, open-label, multicenter studies.
Nulliparous and parous women.
Levonorgestrel intrauterine system 13.5 mg, LNG-IUS 19.5 mg, or LNG-IUS 20 μg/24 h (total content 52 mg).
Pharmacokinetics of LNG, ovulation rate, cervical function, and endometrium effects.
The in vivo LNG release rate of LNG-IUS 13.5 mg was approximately 14 μg/24 h after 24 days, declining progressively to 5 μg/24 h after 3 years. The average LNG serum concentration over 3 years of use was 74.3 ng/L, 114 ng/L, and 218 ng/L for LNG-IUS 13.5 mg, LNG-IUS 19.5 mg, and LNG-IUS 20 μg/24 h, respectively. All treatments showed very similar progestogenic effects on cervical mucus, with low and similar cervical scores throughout treatment. Ovulation was observed in the majority of women in all groups where assessment was possible, although there was a lower incidence of anovulation with LNG-IUS 13.5 mg and LNG-IUS 19.5 mg compared with LNG-IUS 20 μg/24 h. The progestogenic effect on the endometrium was marked in all three LNG-IUS groups.
Levonorgestrel intrauterine system 13.5 mg and LNG-IUS 19.5 mg result in alower systemic exposure to LNG, lower incidence of anovulation, and similar progestin impact on the endometrium and cervical function compared with LNG-IUS 20 μg/24 h.
Summary Background Cervical intraepithelial neoplasia grade 2 or greater (CIN2+) is the surrogate endpoint used in licensure trials of human papillomavirus (HPV) vaccines. Vaccine efficacy against ...CIN3+, the immediate precursor to invasive cervical cancer, is more difficult to measure because of its lower incidence, but provides the most stringent evidence of potential cancer prevention. We report vaccine efficacy against CIN3+ and adenocarcinoma in situ (AIS) in the end-of-study analysis of 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 receive an HPV-16/18 AS04-adjuvanted 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 patients and study investigators were masked to allocated vaccine. The primary endpoint of PATRICIA has been reported previously. In the present end-of-study analysis, we focus on CIN3+ and AIS in the populations of most clinical interest, the total vaccinated cohort (TVC) and the TVC-naive. The TVC comprised all women who received at least one vaccine dose, approximating catch-up populations and including sexually active women (vaccine n=9319; control=9325). The TVC-naive comprised women with no evidence of oncogenic HPV infection at baseline, approximating early adolescent HPV exposure (vaccine n=5824; control=5820). This study is registered with ClinicalTrials.gov , number NCT00122681. Findings Vaccine efficacy against CIN3+ associated with HPV-16/18 was 100% (95% CI 85·5–100) in the TVC-naive and 45·7% (22·9–62·2) in the TVC. Vaccine efficacy against all CIN3+ (irrespective of HPV type in the lesion and including lesions with no HPV DNA detected) was 93·2% (78·9–98·7) in the TVC-naive and 45·6% (28·8–58·7) in the TVC. In the TVC-naive, vaccine efficacy against all CIN3+ was higher than 90% in all age groups. In the TVC, vaccine efficacy against all CIN3+ and CIN3+ associated with HPV-16/18 was highest in the 15–17 year age group and progressively decreased in the 18–20 year and 21–25 year age groups. Vaccine efficacy against all AIS was 100% (31·0–100) and 76·9% (16·0–95·8) in the TVC-naive and TVC, respectively. Serious adverse events occurred in 835 (9·0%) and 829 (8·9%) women in the vaccine and control groups, respectively; only ten events (0·1%) and five events (0·1%), respectively, were considered to be related to vaccination. Interpretation PATRICIA end-of-study results show excellent vaccine efficacy against CIN3+ and AIS irrespective of HPV DNA in the lesion. Population-based vaccination that incorporates the HPV-16/18 vaccine and high coverage of early adolescents might have the potential to substantially reduce the incidence of cervical cancer. Funding GlaxoSmithKline Biologicals.
Summary 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.
Sexual health for adolescents is based on three components: recognizing sexual rights, sexuality education and counseling, and thirdly confidential high quality services. Contraception needs to ...include prevention of both STIs and pregnancies. The first option for adolescents is condoms backed-up by emergency contraception; and later hormonal contraceptives in a longer, mutually monogamous relationship. Condoms and hormonal contraception together can be well recommended for adolescents for dual protection. Long acting reversible contraception (LARC) including both intrauterine contraception and implants are safe and highly effective and thus well suited for adolescents.
Improved contraceptive methods do not automatically lead to reduced numbers of adolescent abortions. When sexuality education, proper counseling and sexual health services are all provided, it is possible to profoundly improve adolescent sexual health.
•Long acting reversible contraception such as intrauterine contraception and implants have much higher contraceptive efficacy, are safe also for adolescents, and should be recommended.•Counselling is the central part of providing contraception for adolescents, pelvic examination is needed only prior to inserting IUC, and not when prescribing COC.•Quick start on any menstrual cycle day is possible for pills, rings, patches and implants, as well as Cu-IUD and LNG-IUS if it is reasonably certain that the patient is not pregnant.•Cu-IUD is the most effective method of emergency contraception. Ulipristal acetate is more effective than levonorgestrel and works for 5 days.
To compare the levonorgestrel intrauterine system (LNG-IUS 8), which has an average levonorgestrel release rate of ∼8 μg/24 hours during the first year (total levonorgestrel content 13.5 mg; ...Jaydess/Skyla), with the etonogestrel (ENG) subdermal implant (total content, 68 mg) with regard to the 12-month discontinuation rate (primary outcome).
Randomized, open-label, phase III study.
Thirty-eight centers in six European countries.
Study population of 766 healthy nulliparous and parous women aged 18-35 years.
The LNG-IUS 8 or the ENG implant.
Discontinuation rate, by treatment group, at Month 12.
The 12-month discontinuation rates were 19.6% and 26.8% in the LNG-IUS 8 and ENG implant groups, respectively. The -7.2% difference was statistically significant (95% confidence interval -13.2%, -1.2%). Fewer women in the LNG-IUS 8 group than in the ENG implant group discontinued because of increased bleeding (3.2% vs. 11.3%) or adverse events (14.3% vs. 21.8%). At 12 months, more women in the LNG-IUS 8 group than in the ENG implant group were "very/somewhat satisfied" with their bleeding pattern (60.9% vs. 33.6%) and reported a preference to use their study treatment after study completion (70.1% vs. 58.5%).
The LNG-IUS 8 was associated with a significantly lower 12-month discontinuation rate compared with the ENG implant; mainly because ENG implant users frequently discontinued due to increased bleeding. More LNG-IUS 8 users than ENG implant users reported being "very/somewhat satisfied" with their bleeding pattern, and reported a preference to continue using their study treatment after the study.
NCT01397097.
Two low-dose levonorgestrel intrauterine contraceptive systems (LNG-IUSs; total content 13.5 mg average approx. 8 μg/24 hours over the first year; LNG-IUS 8 and total content 19.5 mg average approx. ...13 μg/24 hours over the first year; LNG-IUS 13) have previously been shown to be highly effective (3-year Pearl Indices: 0.33 and 0.31, respectively), safe and well tolerated. The present subgroup analyses evaluated whether or not outcomes were affected by parity, age (18-25 vs 26-35 years), or body mass index (BMI, <30 vs ≥30 kg/m2).
Nulliparous and parous women aged 18‒35 years with regular menstrual cycles (21‒35 days) requesting contraception were randomized to 3 years of LNG-IUS 8 or LNG-IUS 13 use.
In the LNG-IUS 8 and LNG-IUS 13 groups, 1432 and 1452 women, respectively, had a placement attempted and were included in the full analysis set; 39.2%, 39.2% and 17.1% were 18-25 years old, nulliparous and had a BMI ≥30 kg/m2, respectively. Both systems were similarly effective regardless of age, parity or BMI; the subgroup Pearl Indices had widely overlapping 95% confidence intervals. Placement of LNG-IUS 8 and LNG-IUS 13 was easier (p < 0.0001) and less painful (p < 0.0001) in women who had delivered vaginally than in women who had not. The complete/partial expulsion rate was 2.2-4.2% across all age and parity subgroups and higher in parous than in nulliparous women (p = 0.004). The incidence of pelvic inflammatory disease was 0.1-0.6% across all age and parity subgroups: nulliparous and younger women were not at higher risk than parous and older women, respectively. The ectopic pregnancy rate was 0.3-0.4% across all age and parity subgroups. Across all age and parity subgroups, the 3-year completion rate was 50.9-61.3% for LNG-IUS 8 and 57.9-61.1% for LNG-IUS 13, and was higher (p = 0.0001) among older than younger women in the LNG-IUS 8 group only.
LNG-IUS 8 and LNG-IUS 13 were highly effective, safe and well tolerated regardless of age or parity.
Clinical trials.gov NCT00528112.
With optimal strategy, human papillomavirus (HPV) vaccines have the potential to control HPV. We have assessed vaccine efficacy (VE), herd effect (HE) of HPV vaccination and overall protective ...effectiveness (PE) against high‐risk HPV infections by HPV type and vaccination strategy in a community‐randomized trial using the bivalent HPV16/18 vaccine. We randomized 33 communities to gender‐neutral HPV vaccination (Arm A), HPV vaccination of girls and hepatitis B‐virus (HBV) vaccination of boys (Arm B) and gender‐neutral HBV vaccination (Arm C). Entire 1992–1995 male (40,852) and female (39,420) birth cohorts were invited, and 11,662 males and 20,513 females vaccinated with 20–30% and 45% coverage in 2007–2010. During 2010–2014, 11,396 cervicovaginal samples were collected from 13,545 18.5‐year‐old attendees. HPV typing was performed by a high‐throughput PCR. VE was calculated for HPV vaccinated women and HE for non‐HPV‐vaccinated women, using the HBV vaccinated, for HE all non‐HPV vaccinated, Arm C women as controls. PE was calculated as coverage rate‐weighted mean of VE + HE. HPV16/18/45 and 31/33/35 VEs varied between 86–94% and 30–66%, respectively. Only the gender‐neutral vaccination provided significant HEs against HPV18 (61%) and HPV31 (72%) in the 1995 birth cohort—increased HEs against HPV33 (39%) and HPV35 (42%) were also observed. Due to the increased HEs, PEs for HPV16/18/45 and HPV31/33/35 were comparable in the gender‐neutral arm 1995 birth cohort. High vaccine efficacy against HPV16/18/45 and, gender‐neutral vaccination‐enforced, herd effect against HPV18/31/33/35 by the bivalent vaccine rapidly provides comparable overall protective effectiveness against six oncogenic HPV types: 16/18/31/33/35/45.
What's new?
Human papillomavirus (HPV) vaccination coverage has remained low to moderate in most countries. An optimal vaccination program should therefore aim to generate herd effect even with low coverage. Here, the authors report results from a community‐randomized trial with low to moderate vaccination coverage comparing the bivalent vaccine efficacy, herd effect, and overall protective effectiveness of gender‐neutral or girls‐only vaccination strategies against up to 16 HPV types with special emphasis on types 16/18/31/33/35/45. High vaccine efficacy against HPV16/18/45 and gender‐neutral vaccination‐enforced herd effect against HPV18/31/33/35 by the bivalent vaccine rapidly provided comparable overall protective effectiveness against six high‐risk HPV types, 16/18/31/33/35/45.
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