Epidemiological Study of Tobacco Use and Human Papillomavirus - Implications for Public Health Prevention

Kohdunkaulan syöpä on yksi naisten yleisimmistä syöpämuodoista. Seksin yhteydessä tarttuvat syöpävaaralliset ihmisen papilloomavirukset (HPV) ovat kohdunkaulansyövän välttämättömiä syytekijöitä. Vain pieni osa HPV-infektioon sairastuneista naisista saa syövän. Muut vältettävissä olevat osatekijät, jotka saavat yhdessä HPV:n kanssa kohdunkaulansyövän esiasteet etenemään on identifioitava ja voitettava. Tupakointi, mahdollinen ympäristöperäinen kohdunkaulansyövän osatekijä, on herättänyt kasvavaa mielenkiintoa 1980-luvulta lähtien. Tarkoitukseni oli tässä työssä määrittää tupakoinnin rooli kohdunkaulansyövässä ja sen esiasteissa sekä HPV-infektioissa, ja arvioida tupakoinnin vaikutusta luonnollisen HPV-infektion ja toisaalta rokotuksen seurauksena syntyneelle immuunivasteelle. Väestöpohjainen upotettu tapaus-verrokkitutkimus hyödynsi viittä pohjoismaista (Islanti, Norja, Ruotsi, Suomi) seerumipankkikohorttia. Tapausten ja verrokkien näytteistä tutkittiin kotiniini (tupakoinnin biomarkkeri) ja HPV, herpes simplex virus ja klamydia vasta-aineet. Pienen otoskoon vuoksi ensimmäisen tutkimusmateriaalin mahdollisuudet erottaa onko tupakointi kohdunkaulan syövän kehittymisen itsenäinen riskitekijä vai selittyykö osuus syöpävaarallisten HPV:n jäännössekoitusvaikutuksella (osajulkaisu I) ei ollut mahdollinen. Toiseen tutkimusmateriaaliin (osajulkaisu I) keräsimme neljä kertaa suuremman, erillisen, materiaalin, jossa oli 588 tapausta ja 2861 verrokkia. Osoitimme tupakoinnin olevan kohdunkaulansyövän itsenäinen riskitekijä. Löysimme erittäin merkitsevän 2-3 kertaisen kohdunkaulansyöpäriskin (vaarasuhde, OR = 2.1; 95 % luottamusväli (CI): 1.4-3.2) ja levyepiteelisyöpäriskin (OR = 2.7; 95% CI: 1.7-4.3) HPV16/18 vasta-ainepositiivisten aktiivisten tupakoitsijoiden joukossa, joka oli vapaa jäännössekoitus-vaikutuksesta. Lisäksi piste-estimaatit olivat sitä suurempia mitä korkeampi tutkittavien ikä oli diagnoosihetkellä (so. mitä pitempi altistuminen) ja mitä korkeampi heidän kotiniinitasonsa. Tekemässämme poikkileikkaustutkimuksessa (osajulkaisu II) vertasimme tupakoitsijoiden ja purutupakan käyttäjien useiden HPV infektioiden ja kohdunkaulansyövän esiasteiden (SIL) riskiä kahdessa populaatiossa. Tutkimuksessa oli 2162 naista Norsunluurannikolta Länsi-Afrikasta ja 419 naista Suomesta, Pohjoi-Euroopasta, joista oli käytettävissä tiedot kohdunkaulansyövän seulontatutkimuksesta, tupakoinnista ja purutupakan käytöstä, kohdunkaulan HPV DNA löydöksistä, klamydia ja HIV vasta-ainetiedot. Molemmissa tutkittavien ryhmissä tupakka-altistus (purutupakan käyttäjillä ja tupakoitsijoilla) liittyi kohonneeseen matala-asteisen SIL-muutoksen riskiin sekä nuoremmilla (OR= 5.5, 95% CI: 1.2-26) että vanhemmilla (OR=5.5, 95% CI: 2.1-14) tutkittavilla. Löysimme, ei-tilastollisesti merkitsevästi, kohonneen matala- ja korkea-asteisten SIL-muutosten riskin yli 30-vuotiailla tupakka-altistuneilla (purutupakan käyttäjät tai tupakoitsijat) tutkittavilla. Heidän useiden HPV-infektioiden riskinsä ei ollut kohonnut. Kohorttitutkimuksessa (osajulkaisu III) arvioimme tupakoinnin liittymistä kiertäviin HPV vasta-aineisiin 191 HPV-infektioon sairastuneella naisella, joita seurattiin aina 10 vuotta kohdunkaulansyövän seulontanäytteillä joista määritettiin myös HPV-DNA.Tutkimuksen alku- ja loppuhetkillä otetut näytteet tutkittiin kotiniini, ja HPV16 ja HPV18 immunoglobuliini (Ig) G ja IgA vasta-aineiden suhteen, myös klamydia vasta-aineet määritettiin ELISA menetelmällä. Nuoret tupakoitsevat naiset serokonvertoivat HPV16/18 viruksille tai säilyttivät nämä vasta-aineensa 10 seurantavuoden ajan vähemmän todennäköisesti kuin tupakoimattomat. Tämä viittaa siihen, että nuorilla naisilla, joilla on syöpävaarallisten HPV16/18 virusten aiheuttama infektio, tupakointi huonontaa vasta-aineresponssia korkean riskin HPV virustyypeille. Kaksoissokkoutettuun, satunnaistettuun faasi III tutkimukseen osallistui Suomessa 4808 16-17 vuotiasta naista, ja he saivat joko HPV16/18 AS04-adjuvantoitua viruksen kaltaisista partikkeleista (VLP) koostuvaa rokotetta tai kontrollina hepatiitti A rokotetta (HavrixTM) (osajulkaisu IV). Teimme pilottitutkimuksen 216 tutkittavan joukossa vertaamalla HPV16/18 vasta-aineita tupakoimattomilla ja tupakoitsijoilla 7 kuukautta rokotuksen aloittamisesta (kuukausi kolmannen rokotuskerran jälkeen). Alkuhetken ja 7 kuukauden seeruminäytteistä analysoitiin kotiniini ja HPV16 ja HPV18 IgG vasta-aineet. Naisilla, jotka tupakoivat ja jotka eivät tupakoineet HPV16 ja HPV18 vasta-aineet olivat samalla tasolla 7 kuukautta rokotuksen jälkeen. Tuloksemme viittaa siihen, että tupakoinnilla ei ole vaikutusta HPV rokotuksen seurauksena syntyvään vasta-aineresponssiin. Tulostemme mukaan HPV-rokotus ja seulontaohjelmia, ja kohdunkaulansyövän varhaista diagnostiikkaa kehitettäessä myös kansanterveystyö tupakoinnin ja purutupakan käytön vähentämiseksi olisi perusteltua, erityisesti nuorilla naisilla.Aline Simen-Kapeu. Epidemiological Study of Tobacco Use and Human Papillomavirus Implications for Public Health Prevention. 150 pages. Cervical cancer (CC) is one of the most common forms of cancer in women. The sexually transmitted oncogenic human papillomavirus (HPV) types are the necessary etiological agents of CC. However, only a small fraction of HPV-infected women go on to develop cancer. Other avoidable co-factors that act in conjunction with HPV to promote cervical malignant lesions need to be verified and tackled. Tobacco exposure, a potential environmental cofactor of CC, has attracted increasing attention since the early 1980s. My aim in this thesis was to assess the role of tobacco exposure in cervical precancerous lesions and cancer of the uterine cervix as well as in multiple HPV infections, and to evaluate the impact of tobacco smoking on the immune response to natural HPV infection as well as to HPV vaccination. A population-based case-control study of CC was nested within a joint cohort of five Nordic serum banks from Finland, Iceland, Norway and Sweden. The samples of cases and controls were analyzed for cotinine (a biomarker of tobacco smoking) and antibodies to HPV types 16 and 18, herpes simplex virus type 2 (HSV-2), and Chlamydia trachomatis (C. trachomatis). Due to small sample size, the first study material (171 cases and 496 controls) (Paper I) had limited power to distinguish whether tobacco smoking was an independent cofactor in cervical carcinogenesis or whether its relative role was due to residual confounding by the oncogenic HPVs. In the second study material (Paper I), we assembled almost four times bigger independent material, including 588 cases and 2,861 controls. We identified smoking as an independent risk factor for CC. A highly significant 2- to 3-fold increased risk of invasive CC (Odds ratio (OR) =2.1; 95% confidence interval (CI): 1.4- 3.2) and squamous cell carcinoma (SCC) (OR =2.7; 95%CI: 1.7- 4.3), free of residual confounding bias, was found among HPV16/18-seropositive heavy smokers. In addition, the point estimates increased with increasing age at diagnosis (probably indicating longer exposure) and increasing cotinine level. In a cross-sectional analysis (Paper II), we compared the association between tobacco smoking and chewing and the risk of multiple HPV infections and cervical squamous intraepithelial lesions (SILs) in two populations with different routes of tobacco exposure. We studied 2,162 women from Côte d Ivoire, West Africa, and 419 women from Finland, Northern Europe, with baseline data on cervical screening, smoking and chewing habits, HPV DNA status, C. trachomatis status and human immunodeficiency virus (HIV) seropositivity. In both settings, tobacco consumers (chewers or smokers) ≥30 years of age tended to have an increased risk of low-grade SIL (LSIL). Among tobacco chewers (Côte d Ivoire), the risk of high grade SIL (HSIL) was five times higher in both young (OR=5.5, 95% CI: 1.2 26) and older (OR=5.5, 95% CI: 2.1 14) women compared to non-chewers. We found an increased, albeit not significant, risk of both LSIL and HSIL, in HPV-DNA positive women ≥30 years of age an! d actively exposed to tobacco through smoking or chewing. There was no increased risk of multiple HPV infections among tobacco consumers. In a cohort study (Paper III), we evaluated the association between humoral immune response to HPV and smoking in 191 HPV infected women prospectively followed-up for 10 years by cytology and HPV DNA analyses. The baseline sample and the last follow-up sample were analysed for serum cotinine levels, Immunoglobulin (Ig) A and IgG antibodies to HPV16 and 18, and C. trachomatis using ELISA methods. Young women ( A phase III double-blind, randomized controlled trial enrolled 4,808 16- to 17-year-old females in Finland to receive either the prophylactic HPV16/18 AS04-adjuvanted vaccine-like-particle (VLP) vaccine or hepatitis A vaccine (HavrixTM) as a control (Paper IV). We conducted a pilot study among 216 participants to compare HPV16/18 antibody levels of nonsmokers and smokers 7 months post-vaccination (one month post the third vaccination dose). Baseline and month 7 serum samples were analysed for cotinine levels and IgG antibodies to HPV16 and 18. We found that women who smoked appeared to have comparable levels of anti-HPV16 and 18 antibodies to nonsmokers at month 7 post-vaccination. Our data suggest that smoking may not have an impact on the humoral antibody response following HPV vaccination. Alongside the development and combination of HPV vaccination programmes and screening and early diagnosis of CC, our findings support public health initiatives intended to prevent tobacco smoking and chewing exposures, particularly among young women

Do improvements in outreach, clinical, and family and community-based services predict improvements in child survival? An analysis of serial cross-sectional national surveys

<p>Abstract</p> <p>Background</p> <p>There are three main service delivery channels: clinical services, outreach, and family and community. To determine which delivery channels are associated with the greatest reductions in under-5 mortality rates (U5MR), we used data from sequential population-based surveys to examine the correlation between changes in coverage of clinical, outreach, and family and community services and in U5MR for 27 high-burden countries.</p> <p>Methods</p> <p>Household survey data were abstracted from serial surveys in 27 countries. Average annual changes (AAC) between the most recent and penultimate survey were calculated for under-five mortality rates and for 22 variables in the domains of clinical, outreach, and family- and community-based services. For all 27 countries and a subset of 19 African countries, we conducted principal component analysis to reduce the variables into a few components in each domain and applied linear regression to assess the correlation between changes in the principal components and changes in under-five mortality rates after controlling for multiple potential confounding factors.</p> <p>Results</p> <p>AAC in under 5-mortality varied from 6.6% in Nepal to -0.9% in Kenya, with six of the 19 African countries all experiencing less than a 1% decline in mortality. The strongest correlation with reductions in U5MR was observed for access to clinical services (all countries: p = 0.02, r²= 0.58; 19 African countries p < 0.001, r²= 0.67). For outreach activities, AAC U5MR was significantly correlated with antenatal care and family planning services, while AAC in immunization services showed no association. In the family- and community services domain, improvements in breastfeeding were associated with significant changes in mortality in the 30 countries but not in the African subset; while in the African countries, nutritional status improvements were associated with a significant decline in mortality.</p> <p>Conclusions</p> <p>Our findings support the importance of increasing access to clinical services, certain outreach services and breastfeeding and, in Africa, of improving nutritional status. Integrated programs that emphasize these services may lead to substantial mortality declines.</p

Quality care during labour and birth: a multi-country analysis of health system bottlenecks and potential solutions

BACKGROUND: Good outcomes during pregnancy and childbirth are related to availability, utilisation and effective implementation of essential interventions for labour and childbirth. The majority of the estimated 289,000 maternal deaths, 2.8 million neonatal deaths and 2.6 million stillbirths every year could be prevented by improving access to and scaling up quality care during labour and birth. METHODS: The bottleneck analysis tool was applied in 12 countries in Africa and Asia as part of the Every Newborn Action Plan process. Country workshops engaged technical experts to complete the survey tool, which is designed to synthesise and grade health system "bottlenecks", factors that hinder the scale up, of maternal-newborn intervention packages. We used quantitative and qualitative methods to analyse the bottleneck data, combined with literature review, to present priority bottlenecks and actions relevant to different health system building blocks for skilled birth attendance and basic and comprehensive emergency obstetric care. RESULTS: Across 12 countries the most critical bottlenecks identified by workshop participants for skilled birth attendance were health financing (10 out of 12 countries) and health workforce (9 out of 12 countries). Health service delivery bottlenecks were found to be the most critical for both basic and comprehensive emergency obstetric care (9 out of 12 countries); health financing was identified as having critical bottlenecks for comprehensive emergency obstetric care (9 out of 12 countries). Solutions to address health financing bottlenecks included strengthening national financing mechanisms and removing financial barriers to care seeking. For addressing health workforce bottlenecks, improved human resource planning is needed, including task shifting and improving training quality. For health service delivery, proposed solutions included improving quality of care and establishing public private partnerships. CONCLUSIONS: Progress towards the 2030 targets for ending preventable maternal and newborn deaths is dependent on improving quality of care during birth and the immediate postnatal period. Strengthening national health systems to improve maternal and newborn health, as a cornerstone of universal health coverage, will only be possible by addressing specific health system bottlenecks during labour and birth, including those within health workforce, health financing and health service delivery

Basic newborn care and neonatal resuscitation: a multi-country analysis of health system bottlenecks and potential solutions.

BACKGROUND: An estimated two-thirds of the world's 2.7 million newborn deaths could be prevented with quality care at birth and during the postnatal period. Basic Newborn Care (BNC) is part of the solution and includes hygienic birth and newborn care practices including cord care, thermal care, and early and exclusive breastfeeding. Timely provision of resuscitation if needed is also critical to newborn survival. This paper describes health system barriers to BNC and neonatal resuscitation and proposes solutions to scale up evidence-based strategies. METHODS: The maternal and newborn bottleneck analysis tool was applied by 12 countries in Africa and Asia as part of the Every Newborn Action Plan process. Country workshops engaged technical experts to complete the survey tool, which is designed to synthesise and grade health system "bottlenecks" that hinder the scale up of maternal-newborn intervention packages. We used quantitative and qualitative methods to analyse the bottleneck data, combined with literature review, to present priority bottlenecks and actions relevant to different health system building blocks for BNC and neonatal resuscitation. RESULTS: Eleven of the 12 countries provided grading data. Overall, bottlenecks were graded more severely for resuscitation. The most severely graded bottlenecks for BNC were health workforce (8 of 11 countries), health financing (9 out of 11) and service delivery (7 out of 9); and for neonatal resuscitation, workforce (9 out of 10), essential commodities (9 out of 10) and service delivery (8 out of 10). Country teams from Africa graded bottlenecks overall more severely. Improving workforce performance, availability of essential commodities, and well-integrated health service delivery were the key solutions proposed. CONCLUSIONS: BNC was perceived to have the least health system challenges among the seven maternal and newborn intervention packages assessed. Although neonatal resuscitation bottlenecks were graded more severe than for BNC, similarities particularly in the workforce and service delivery building blocks highlight the inextricable link between the two interventions and the need to equip birth attendants with requisite skills and commodities to assess and care for every newborn. Solutions highlighted by country teams include ensuring more investment to improve workforce performance and distribution, especially numbers of skilled birth attendants, incentives for placement in challenging settings, and skills-based training particularly for neonatal resuscitation

Treatment of neonatal infections: a multi-country analysis of health system bottlenecks and potential solutions.

BACKGROUND: Around one-third of the world's 2.8 million neonatal deaths are caused by infections. Most of these deaths are preventable, but occur due to delays in care-seeking, and access to effective antibiotic treatment with supportive care. Understanding variation in health system bottlenecks to scale-up of case management of neonatal infections and identifying solutions is essential to reduce mortality, and also morbidity. METHODS: A standardised bottleneck analysis tool was applied in 12 countries in Africa and Asia as part of the development of the Every Newborn Action Plan. Country workshops involved technical experts to complete a survey tool, to grade health system "bottlenecks" hindering scale up of maternal-newborn intervention packages. Quantitative and qualitative methods were used to analyse the data, combined with literature review, to present priority bottlenecks and synthesise actions to improve case management of newborn infections. RESULTS: For neonatal infections, the health system building blocks most frequently graded as major or significant bottlenecks, irrespective of mortality context and geographical region, were health workforce (11 out of 12 countries), and community ownership and partnership (11 out of 12 countries). Lack of data to inform decision making, and limited funding to increase access to quality neonatal care were also major challenges. CONCLUSIONS: Rapid recognition of possible serious bacterial infection and access to care is essential. Inpatient hospital care remains the first line of treatment for neonatal infections. In situations where referral is not possible, the use of simplified antibiotic regimens for outpatient management for non-critically ill young infants has recently been reported in large clinical trials; WHO is developing a guideline to treat this group of young infants. Improving quality of care through more investment in the health workforce at all levels of care is critical, in addition to ensuring development and dissemination of national guidelines. Improved information systems are needed to track coverage and adequately manage drug supply logistics for improved health outcomes. It is important to increase community ownership and partnership, for example through involvement of community groups

Inpatient care of small and sick newborns: a multi-country analysis of health system bottlenecks and potential solutions.

BACKGROUND: Preterm birth is the leading cause of child death worldwide. Small and sick newborns require timely, high-quality inpatient care to survive. This includes provision of warmth, feeding support, safe oxygen therapy and effective phototherapy with prevention and treatment of infections. Inpatient care for newborns requires dedicated ward space, staffed by health workers with specialist training and skills. Many of the estimated 2.8 million newborns that die every year do not have access to such specialised care. METHODS: The bottleneck analysis tool was applied in 12 countries in Africa and Asia as part of the Every Newborn Action Plan process. Country workshops involved technical experts to complete the survey tool, which is designed to synthesise and grade health system "bottlenecks" (or factors that hinder the scale up) of maternal-newborn intervention packages. For this paper, we used quantitative and qualitative methods to analyse the bottleneck data, and combined these with literature review, to present priority bottlenecks and actions relevant to different health system building blocks for inpatient care of small and sick newborns. RESULTS: Inpatient care of small and sick newborns is an intervention package highlighted by all country workshop participants as having critical health system challenges. Health system building blocks with the highest graded (significant or major) bottlenecks were health workforce (10 out of 12 countries) and health financing (10 out of 12 countries), followed by community ownership and partnership (9 out of 12 countries). Priority actions based on solution themes for these bottlenecks are discussed. CONCLUSIONS: Whilst major bottlenecks to the scale-up of quality inpatient newborn care are present, effective solutions exist. For all countries included, there is a critical need for a neonatal nursing cadre. Small and sick newborns require increased, sustained funding with specific insurance schemes to cover inpatient care and avoid catastrophic out-of-pocket payments. Core competencies, by level of care, should be defined for monitoring of newborn inpatient care, as with emergency obstetric care. Rather than fatalism that small and sick newborns will die, community interventions need to create demand for accessible, high-quality, family-centred inpatient care, including kangaroo mother care, so that every newborn can survive and thrive

Scaling up quality care for mothers and newborns around the time of birth: an overview of methods and analyses of intervention-specific bottlenecks and solutions.

BACKGROUND: The Every Newborn Action Plan (ENAP) and Ending Preventable Maternal Mortality targets cannot be achieved without high quality, equitable coverage of interventions at and around the time of birth. This paper provides an overview of the methodology and findings of a nine paper series of in-depth analyses which focus on the specific challenges to scaling up high-impact interventions and improving quality of care for mothers and newborns around the time of birth, including babies born small and sick. METHODS: The bottleneck analysis tool was applied in 12 countries in Africa and Asia as part of the ENAP process. Country workshops engaged technical experts to complete a tool designed to synthesise "bottlenecks" hindering the scale up of maternal-newborn intervention packages across seven health system building blocks. We used quantitative and qualitative methods and literature review to analyse the data and present priority actions relevant to different health system building blocks for skilled birth attendance, emergency obstetric care, antenatal corticosteroids (ACS), basic newborn care, kangaroo mother care (KMC), treatment of neonatal infections and inpatient care of small and sick newborns. RESULTS: The 12 countries included in our analysis account for the majority of global maternal (48%) and newborn (58%) deaths and stillbirths (57%). Our findings confirm previously published results that the interventions with the most perceived bottlenecks are facility-based where rapid emergency care is needed, notably inpatient care of small and sick newborns, ACS, treatment of neonatal infections and KMC. Health systems building blocks with the highest rated bottlenecks varied for different interventions. Attention needs to be paid to the context specific bottlenecks for each intervention to scale up quality care. Crosscutting findings on health information gaps inform two final papers on a roadmap for improvement of coverage data for newborns and indicate the need for leadership for effective audit systems. CONCLUSIONS: Achieving the Sustainable Development Goal targets for ending preventable mortality and provision of universal health coverage will require large-scale approaches to improving quality of care. These analyses inform the development of systematic, targeted approaches to strengthening of health systems, with a focus on overcoming specific bottlenecks for the highest impact interventions

Impact of smoking on the quantity and quality of antibodies induced by human papillomavirus type 16 and 18 AS04-adjuvanted virus-like-particle vaccine - a pilot study

Peer reviewe

Antenatal corticosteroids for management of preterm birth: a multi-country analysis of health system bottlenecks and potential solutions.

BACKGROUND: Preterm birth complications are the leading cause of deaths for children under five years. Antenatal corticosteroids (ACS) are effective at reducing mortality and serious morbidity amongst infants born at 75%) reported very major or significant bottlenecks. Health information systems should include improved gestational age assessment and track ACS coverage, use and outcomes. Better health service delivery requires clarified policy assigning roles by level of care and cadre of provider, dependent on capability to assess gestational age and risk of preterm birth, and the implementation of guidelines with adequate supervision, mentoring and quality improvement systems, including audit and feedback. National essential medicines lists should include dexamethasone for antenatal use, and dexamethasone should be integrated into supply logistics

Antenatal corticosteroids for management of preterm birth: a multi-country analysis of health system bottlenecks and potential solutions

BackgroundPreterm birth complications are the leading cause of deaths for children under five years. Antenatal corticosteroids (ACS) are effective at reducing mortality and serious morbidity amongst infants born at 75%) reported very major or significant bottlenecks. Health information systems should include improved gestational age assessment and track ACS coverage, use and outcomes. Better health service delivery requires clarified policy assigning roles by level of care and cadre of provider, dependent on capability to assess gestational age and risk of preterm birth, and the implementation of guidelines with adequate supervision, mentoring and quality improvement systems, including audit and feedback. National essential medicines lists should include dexamethasone for antenatal use, and dexamethasone should be integrated into supply logistics