Summary 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.
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.
Objective: Nitric oxide synthase inhibition has anti-angiogenic properties. Magnetic resonance (MR) imaging was used to image the functional significance of these microvascular changes in a rat model ...of chronic ischemic myocardium in vivo.
Methods: The authors quantitatively determined myocardial perfusion and regional blood volume, left ventricular geometry, and function using MR imaging. Animals received either L-NAME + hydralazine or no treatment and were investigated 1 and 2 weeks after induction of coronary artery stenosis or sham operation at rest and during vasodilatation. Double-labeling immunohistochemistry was used to visualize angiogenesis and to compare with data obtained by MR imaging.
Results: Left ventricular mass and end-diastolic volumes were comparable in both groups 2 weeks after treatment. However, basal and maximum perfusion in animals with L-NAME + hydralazine treatment were reduced compared to animals not treated (p < .05). Basal regional blood volume remained constant in all groups, whereas maximum regional blood volume was reduced by L-NAME + hydralazine (p < .05). Endothelial cell proliferation, a direct marker for angiogenesis, was reduced by L-NAME + hydralazine (p < .01). Conclusions: MR imaging allows noninvasive quantification of functional microcirculation and angiogenesis in the rat heart in vivo. Nitric oxide synthase blockade results in changes in functional microcirculation and in an inhibition of angiogenesis in both ischemic and nonischemic myocardial tissue.
Microcirculation (2005) 12, 339-347. doi:10.1080/10739680590934754
