No abstract

In developing countries, risk of human papillomavirus (HPV) infection may be increased by the high prevalence of human immunodeficiency virus (HIV) infection. We evaluated the safety and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine in HIV-infected women in South Africa. Asymptomatic HIV-positive women aged 18-25 years (N=120) were stratified by CD4⁺ T-cell count and randomised (1:1) to receive HPV-16/18 vaccine (Cervarix®; GlaxoSmithKline Vaccines) or placebo (Al[OH]3) at 0, 1 and 6 months (double-blind). HIV-negative women (N=30) received HPV-16/18 vaccine (open label). Anti-HPV-16/18 antibody and CD4⁺ T-cell responses, CD4⁺ T-cell count, HIV viral load, HIV clinical stage and safety were evaluated for 12 months. The safety and reactogenicity profile of the HPV-16/18 vaccine was comparable in HIV-positive and HIV-negative women. Irrespective of baseline HPV status, all HIV-positive and HIV-negative women who received the HPV-16/18 vaccine were seropositive for both HPV-16 and HPV-18 after the second vaccine dose (month 2) and remained seropositive for both antigens at month 12. Anti-HPV-16/18 antibody titres at month 12 remained substantially above levels associated with natural infection. The HPV-16/18 vaccine induced sustained anti-HPV-16/18 CD4⁺ T-cell responses in both HIV-positive and HIV-negative women. No impact of baseline CD4⁺ T-cell count or HIV viral load was observed on the magnitude of the immune response in HIV-positive women. In HIV-positive women, CD4⁺ T-cell count, HIV viral load and HIV clinical stage were unaffected by HPV-16/18 vaccine administration. In conclusion, the HPV-16/18 AS04-adjuvanted vaccine appears immunogenic and well-tolerated in women with HIV infection. Study ID: 107863/NCT00586339.

OBJECTIVES: To assess the weight-reducing effects and tolerability of 5 mg, 10 mg and 15 mg daily doses of sibutramine, a novel serotonin and noradrenaline reuptake inhibitor (SNRI). DESIGN: Multicentre, double-blind, and placebo-controlled study. After a one week run-in period, patients were randomized to receive placebo or sibutramine over a 12-week period. Advice on diet and behaviour modi®cation was provided. One follow-up was conducted four weeks after cessation of treatment. SUBJECTS: 235 obese outpatients, aged 18±65 y with a body mass index (BMI) within the range 27±40 kgam 2 . MEASUREMENTS: Weight, height, waist and hip circumference, and medical history, assessment of hunger, satiety, appetite and craving for sweet, savoury and carbohydrate foods, and also for carbohydrate snacking, standard laboratory assessments, blood pressure, heart rate and ECG. RESULTS: The group mean ( AE s.e.m.) weight loss at end-point was 1.4 AE 0.5 kg for placebo (n 59), 2.4 AE 0.5 kg for 5 mg sibutramine (n 56), 5.1 AE 0.5 kg for 10 mg sibutramine (n 59) and 4.9 AE 0.5 kg (n 62) for 15 mg sibutramine. The difference observed between the placebo and the 10 mg and 15 mg groups was statistically signi®cant from week 2 onwards (P`0.01), but there was no signi®cant difference between these sibutramine groups. The percentage of patients losing b 5% of initial bodyweight was signi®cantly greater for 15 mg sibutramine (55%) and 10 mg sibutramine (49%) than for treatment with placebo (19%), (P`0.001). During the double-blind period, 41 patients (17%) withdrew prematurely and 168 patients (71%) reported 453 adverse events. The incidence and type of adverse event and the rates of withdrawal, were not signi®cantly different in the four groups. No signi®cant differences between the groups were observed, in respect of changes in systolic and diastolic blood pressure, but a signi®cant increase in heart rate (about 4 beatsamin) was noted for patients who received 10 mg or 15 mg sibutramine, compared with the placebo (P`0.001).CONCLUSION: These data demonstrate dose-related weight loss with sibutramine treatment for up to 12 weeks in obese patients. Doses of 10 mg and 15 mg once daily were shown to be similarly effective, well tolerated and signi®cantly more effective than the placebo.

Background. Cervical cancer is a major public health problem for women in sub-Saharan Africa. Availability of a human papillomavirus (HPV) vaccine could have an important public health impact.Methods. In this phase IIIb, double-blind, randomized, placebo-controlled, multicenter trial (NCT00481767), healthy African girls and young women seronegative for human immunodeficiency virus (HIV) were stratified by age (10–14 or 15–25 years) and randomized (2:1) to receive either HPV-16/18 AS04-adjuvanted vaccine (n = 450) or placebo (n = 226) at 0, 1, and 6 months. The primary objective was to evaluate HPV-16/18 antibody responses at month 7. Seropositivity rates and corresponding geometric mean titers (GMTs) were measured by enzyme-linked immunosorbent assay.Results. In the according-to-protocol analysis at month 7, 100% of initially seronegative participants in the vaccine group were seropositive for both anti–HPV-16 and anti–HPV-18 antibodies (n = 130 and n = 128 for 10–14-year-olds, respectively; n = 190 and n = 212 for 15–25-year-olds). GMTs for HPV-16 and HPV-18 were higher in 10–14-year-olds (18 423 [95% confidence interval, 16 185–20 970] and 6487 [5590–7529] enzyme-linked immunosorbent assay units (EU)/mL, respectively) than in 15–25-year-olds (10 683 [9567–11 930] and 3743 [3400–4120] EU/mL, respectively). Seropositivity was maintained at month 12. No participant withdrew owing to adverse events. No vaccine-related serious adverse events were reported.Conclusions. The HPV-16/18 AS04-adjuvanted vaccine was highly immunogenic and had a clinically acceptable safety profile when administered to healthy HIV-seronegative African girls and young women.

This randomized, partially-blind study (ClinicalTrials.gov registration number NCT00541970) evaluated the immunogenicity and safety of 2-dose (2D) schedules of the HPV-16/18 AS04-adjuvanted vaccine. Results to month (M) 24 have been reported previously and we now report data to M48 focusing on the licensed vaccine formulation (20 μg each of HPV-16 and -18 antigens) administered at M0,6 compared with the standard 3-dose (3D) schedule (M0,1,6). Healthy females (age stratified: 9–14, 15–19, 20–25 years) were randomized to receive 2D at M0,6 (n = 240) or 3D at M0,1,6 (n = 239). In the according-to-protocol immunogenicity cohort, all initially seronegative subjects seroconverted for HPV-16 and -18 antibodies and remained seropositive up to M48. For both HPV-16 and -18, geometric mean antibody titer (GMT) ratios (3D schedule in women aged 15–25 years divided by 2D schedule in girls aged 9–14 years) at M36 and M48 were close to 1, as they were at M7 when non-inferiority was demonstrated. The kinetics of HPV-16, -18, -31, and -45 antibody responses were similar for both groups and HPV-16 and -18 GMTs were substantially higher than natural infection titers. The vaccine had a clinically acceptable safety profile in both groups. In summary, antibody responses to a 2D M0,6 schedule of the licensed vaccine formulation in girls aged 9–14 years appeared comparable to the standard 3D schedule in women aged 15–25 years up to 4 years after first vaccination. A 2D schedule could facilitate implementation of HPV vaccination programs and improve vaccine coverage and series completion rates.