Is one dose of human papillomavirus vaccine as effective as three?: A national cohort analysis.

AIM: Prophylactic human papillomavirus (HPV) vaccines are highly effective at preventing pre-cancerous cervical lesions when given in a three-dose schedule. Some post-hoc trial data suggest that one dose prevents HPV infection. If one dose could prevent pre-cancerous cervical lesions, then global cervical cancer prevention would be greatly facilitated. We assessed the effectiveness of quadrivalent HPV vaccine by number of doses against cervical intraepithelial neoplasia (CIN) 2 or 3/adenocarcinoma-in-situ (AIS)/cancer in Australia up to seven years post vaccination. METHODS: We linked registry data from all 8 jurisdictional cervical screening registers, with the national HPV vaccination register, death index and cancer registers for all Australian women aged 15 or under when eligible for vaccine who screened between April 2007 (when vaccination commenced) and 31 December 2014. We performed Cox proportional hazard regression, adjusted a priori for age, socioeconomic status, and area of residence, to estimate hazard ratios of histologically confirmed CIN2/CIN3/AIS/cancer. RESULTS: We included 250,648 women: 48,845 (19·5%) unvaccinated, 174,995 (69·8%) had received three doses, 18,190 (7·3%) two doses and 8,618 (3·4%) one dose. The adjusted hazard ratio was significantly lower for all dose groups compared to unvaccinated women (1 dose 0·65 (95%CI 0·52-0·81), 2 doses 0·61 (0·52-0·72) and 3 doses 0·59 (0·54-0·65).) With adjustment for age at vaccination amongst the vaccinated group, the adjusted hazard ratios for one dose and two dose recipients were comparable to three dose recipients (one dose 1.01 (95%CI 0.81-1.26), two doses 1.00 (0.85-1.17).) Multiple sensitivity analyses, including use of different dose assignment methods, produced consistent findings. Comparison with a historical cohort of age matched women showed that the result was not due to herd protection alone. CONCLUSIONS: One dose had comparable effectiveness as two or three doses in preventing high-grade disease in a high coverage setting. These findings support the hypothesis that one dose vaccination may be a viable strategy when working towards the global elimination of cervical cancer.

Cervical cancer in women under 25 years of age in Queensland, Australia: To what extent is the diagnosis made by screening cytology?

INTRODUCTION: The current Australian National Cervical Screening Program (NCSP) involves biennial, cytology-based screening of women from the age of 18 years. From December, 2017 this will change to a five-yearly human papilloma virus-based screening commencing at age 25. There is some concern that the new program may delay the opportunistic detection of cervical cancers in women under 25 years. AIM: (1) To review all cases of invasive cervical cancer in Queensland women under the age of 25 over the last 28 years. (2) To determine symptoms and screening history prior to diagnosis. METHODS: A retrospective cohort study was undertaken at the Queensland Centre for Gynaecological Cancer (QCGC) and the Queensland Cancer Registry (QCR) of all women aged between 13 and 25 years diagnosed with cervical cancer in Queensland between 1984 and 2012. Demographic data and symptoms prior to diagnosis were extracted from the QCGC and QCR databases. RESULTS: A total of 56 women aged 13-25, were diagnosed with cervical cancer and treated at the QCGC between 1984 and 2012. The commonest reason for the diagnosis of cancer was investigation of abnormal symptoms (n = 22, 39%) rather than routine Pap smear abnormalities (n = 15, 26%). CONCLUSIONS: Consistent with the world literature, there is a very low incidence of cervical cancer in women under 25 years of age, irrespective of the age of commencement of screening, or the screening interval. Our study lends some support to the proposed commencement age of 25 years in the new NCSP.

Cervical screening rates for women vaccinated against human papillomavirus.

OBJECTIVE: To compare cervical screening rates for women vaccinated with a quadrivalent human papillomavirus (HPV) vaccine with those for unvaccinated women, to address concerns that vaccinated women may not be participating in cervical screening. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional analysis of linked data from the Victorian Cervical Cytology Registry and the National HPV Vaccination Program Register for 20-29-year-old women in Victoria, Australia, for the period 1 January 2009 to 31 December 2011. MAIN OUTCOME MEASURES: Screening participation rates for vaccinated and unvaccinated women. RESULTS: Participation in cervical screening during the 2-year period 2010-2011 was significantly lower in 20-24-year-old vaccinated women compared with unvaccinated women of the same age (37.6% v 47.7%, a 10.1 percentage point difference [95% CI, 9.7-10.6]; P < 0.001) and significantly lower in 25-29-year-old vaccinated women compared with unvaccinated women of the same age (45.2% v 58.7%, a 13.5 percentage point difference [95% CI, 13.1%-13.9%]; P < 0.001). Similar results were observed for participation during the 3-year period 2009-2011. CONCLUSIONS: Despite education messages provided to young women, our results suggest that vaccinated women are being screened at lower rates than unvaccinated women in Australia. While some degree of undermatching of women in the study may have occurred, this cannot wholly explain our findings. Effective implementation of Individual Healthcare Identifiers to health records, including registry records, is needed to prevent potential undermatching of individuals in future linkage studies. In the meantime, efforts to increase participation in cervical screening by vaccinated women are needed.

Impact of a population-based HPV vaccination program on cervical abnormalities: a data linkage study.

BACKGROUND: Australia was one of the first countries to introduce a publicly funded national human papillomavirus (HPV) vaccination program that commenced in April 2007, using the quadrivalent HPV vaccine targeting 12- to 13-year-old girls on an ongoing basis. Two-year catch-up programs were offered to 14- to 17- year-old girls in schools and 18- to 26-year-old women in community-based settings. We present data from the school-based program on population-level vaccine effectiveness against cervical abnormalities in Victoria, Australia. METHODS: Data for women age-eligible for the HPV vaccination program were linked between the Victorian Cervical Cytology Registry and the National HPV Vaccination Program Register to create a cohort of screening women who were either vaccinated or unvaccinated. Entry into the cohort was 1 April 2007 or at first Pap test for women not already screening. Vaccine effectiveness (VE) and hazard ratios (HR) for cervical abnormalities by vaccination status between 1 April 2007 and 31 December 2011 were calculated using proportional hazards regression. RESULTS: The study included 14,085 unvaccinated and 24,871 vaccinated women attending screening who were eligible for vaccination at school, 85.0% of whom had received three doses. Detection rates of histologically confirmed high-grade (HG) cervical abnormalities and high-grade cytology (HGC) were significantly lower for vaccinated women (any dose) (HG 4.8 per 1,000 person-years, HGC 11.9 per 1,000 person-years) compared with unvaccinated women (HG 6.4 per 1,000 person-years, HGC 15.3 per 1,000 person-years) HR 0.72 (95% CI 0.58 to 0.91) and HR 0.75 (95% CI 0.65 to 0.87), respectively. The HR for low-grade (LG) cytological abnormalities was 0.76 (95% CI 0.72 to 0.80). VE adjusted a priori for age at first screening, socioeconomic status and remoteness index, for women who were completely vaccinated, was greatest for CIN3+/AIS at 47.5% (95% CI 22.7 to 64.4) and 36.4% (95% CI 9.8 to 55.1) for women who received any dose of vaccine, and was negatively associated with age. For women who received only one or two doses of vaccine, HRs for HG histology were not significantly different from 1.0, although the number of outcomes was small. CONCLUSION: A population-based HPV vaccination program in schools significantly reduced cervical abnormalities for vaccinated women within five years of implementation, with the greatest vaccine effectiveness observed for the youngest women.

Cytology and cervical cancer surveillance in an era of human papillomavirus vaccination.

Cytological and cancer surveillance will provide the most effective indications of short-term effects and long-term outcomes of the introduction of the human papillomavirus (HPV) vaccine in Australia. This article outlines how this surveillance is proposed to occur through the established national monitoring mechanisms of the National Cervical Screening Program in the annual Australian Institute of Health and Welfare (AIHW) publication 'Cervical screening in Australia'. Cytological surveillance will be possible principally through cytology data provided annually by the state and territory cervical cytology registers, and it is expected that these data will provide the earliest and most comprehensive indications of effects from the HPV vaccine. Some potential issues in interpreting these data are also discussed, including the potentially confounding effects of the introduction of new National Health and Medical Research Council guidelines 'Screening to prevent cervical cancer: guidelines for the management of asymptomatic women with screen-detected abnormalities' some 9 months before the introduction of the vaccine. Cancer surveillance over the long term will be possible using cervical cancer incidence data reported annually for the National Cervical Screening Program in 'Cervical screening in Australia' using data sourced from the Australian Cancer Database. In a final discourse, the HPV vaccine and cervical screening are discussed concurrently, and the importance of continued cervical screening in the HPV vaccine era emphasised.

Sickness behaviour pushed too far--the basis of the syndrome seen in severe protozoal, bacterial and viral diseases and post-trauma.

Certain distinctive components of the severe systemic inflammatory syndrome are now well-recognized to be common to malaria, sepsis, viral infections, and post-trauma illness. While their connection with cytokines has been appreciated for some time, the constellation of changes that comprise the syndrome has simply been accepted as an empirical observation, with no theory to explain why they should coexist. New data on the effects of the main pro-inflammatory cytokines on the genetic control of sickness behaviour can be extended to provide a rationale for why this syndrome contains many of its accustomed components, such as reversible encephalopathy, gene silencing, dyserythropoiesis, seizures, coagulopathy, hypoalbuminaemia and hypertriglyceridaemia. It is thus proposed that the pattern of pathology that comprises much of the systemic inflammatory syndrome occurs when one of the usually advantageous roles of pro-inflammatory cytokines--generating sickness behaviour by moderately repressing genes (Dbp, Tef, Hlf, Per1, Per2 and Per3, and the nuclear receptor Rev-erbalpha) that control circadian rhythm--becomes excessive. Although reversible encephalopathy and gene silencing are severe events with potentially fatal consequences, they can be viewed as having survival advantages through lowering energy demand. In contrast, dyserythropoiesis, seizures, coagulopathy, hypoalbuminaemia and hypertriglyceridaemia may best be viewed as unfortunate consequences of extreme repression of these same genetic controls when the pro-inflammatory cytokines that cause sickness behaviour are produced excessively. As well as casting a new light on the previously unrationalized coexistence of these aspects of systemic inflammatory diseases, this concept is consistent with the case for a primary role for inflammatory cytokines in their pathogenesis across this range of diseases.

Systemic release of high mobility group box 1 protein during severe murine influenza.

Hypercytokinemia is gaining recognition as the mechanism of fatality from influenza. No work to date has addressed the role of high mobility group box 1 protein (HMGB1) in influenza, the parallel being that in other severe proinflammatory cytokine syndromes (e.g., sepsis and malaria) levels of circulating HMGB1 are elevated and may correlate with death. Using a commercially available ELISA for HMGB1, we found that HMGB1 was not increased in the plasma of influenza virus-infected mice (A/Japan/305/57) on day 7 post infection, about the time of peak mortality, and peak levels of HMGB1 in the plasma did not occur until relatively late in infection, on day 9 post infection. In keeping with the late peak of HMGB1 being unassociated with mortality, administration of ethyl pyruvate, which inhibits active secretion but not passive release of HMGB1, to influenza virus-infected mice, did not affect their survival. Further work is required to determine whether influenza virus infection induces passive release of HMGB1, and whether HMGB1 neutralization with a specific Ab would improve survival.

Understanding the role of inflammatory cytokines in malaria and related diseases.

It is now broadly accepted for infectious disease in general that it is not the invading organism, but the body's unbridled response to it--the "cytokine storm"--that causes illness and pathology. Nevertheless, many researchers still regard the harmful effects of falciparum malaria as being governed by oligaemic hypoxia arising from parasitised erythrocytes obstructing blood flow through vulnerable organs, particularly the brain, and we summarise why these notions are no longer tenable. In our view, this harmful sequestration is readily accommodated within the cytokine storm perspective as one of its secondary effects. We approach these issues by examining aspects of malaria, sepsis and influenza in parallel, and discuss the insights that comparisons of the literature can provide on the validity of possible anti-disease therapies.

Increased survival after gemfibrozil treatment of severe mouse influenza.

Gemfibrozil, an agent that inhibits production of proinflammatory cytokines in addition to its clinically useful lipid-lowering activity, increased survival in BALB/c mice that were already ill from infection by influenza virus A/Japan/305/57 (H2N2). Gemfibrozil was administered intraperitoneally once daily from days 4 to 10 after intranasal exposure to the virus. Survival increased from 26% in vehicle-treated mice (n = 50) to 52% in mice given gemfibrozil at 60 mg/kg/day (n = 46) (P = 0.0026). If this principle translates to patients, a drug already approved for human use, albeit by a different route for another purpose, might be adapted relatively fast for use against influenza, conceivably including human infection with a derivative of the avian H5N1 strain.

Human malarial disease: a consequence of inflammatory cytokine release.

Malaria causes an acute systemic human disease that bears many similarities, both clinically and mechanistically, to those caused by bacteria, rickettsia, and viruses. Over the past few decades, a literature has emerged that argues for most of the pathology seen in all of these infectious diseases being explained by activation of the inflammatory system, with the balance between the pro and anti-inflammatory cytokines being tipped towards the onset of systemic inflammation. Although not often expressed in energy terms, there is, when reduced to biochemical essentials, wide agreement that infection with falciparum malaria is often fatal because mitochondria are unable to generate enough ATP to maintain normal cellular function. Most, however, would contend that this largely occurs because sequestered parasitized red cells prevent sufficient oxygen getting to where it is needed. This review considers the evidence that an equally or more important way ATP deficiency arises in malaria, as well as these other infectious diseases, is an inability of mitochondria, through the effects of inflammatory cytokines on their function, to utilise available oxygen. This activity of these cytokines, plus their capacity to control the pathways through which oxygen supply to mitochondria are restricted (particularly through directing sequestration and driving anaemia), combine to make falciparum malaria primarily an inflammatory cytokine-driven disease.

Absence of erythrocyte sequestration in a case of babesiosis in a splenectomized human patient.

BACKGROUND: The importance of vascular occlusion in the pathogenesis of human haemoprotozoal disease is unresolved. METHODS: Giemsa-stained tissue sections from a human case of Babesia microti infection in a splenectomized patient with chronic lymphocytic leukaemia and colon cancer were examined to ascertain the distribution of parasitized erythrocytes within the vascular lumen. RESULTS: No evidence of sequestration was observed. CONCLUSION: This first report on the vascular location of B. microti in human tissue suggests that severe multi-organ failure due to babesiosis is independent of sequestration of parasitized erythrocytes. A similar pathogenesis may also cause multi-organ failure in other intraerythrocytic protozoal infections, including falciparum malaria.