Calculated and structure related activities for drugs with CNS activity [5].
\r\n\tTherefore, the objective of this book is to provide an outlook of the present research on Applied Geomorphology in different parts of the world, highlighting the main challenges mankind faces on this subject. The debate on future perspectives of anthropogenic impacts on the Earth surface and systems, the evolution of concepts on Applied Geomorphology, processes and landforms evaluation and modeling, recurring to recent technologies and methods, geomorphological hazard analysis, as well as strategies for landform conservation and promotion (for non-extractive and destructive activities, e.g. geotourism), are also objectives to pursuit on this book.
",isbn:"978-1-80356-423-4",printIsbn:"978-1-80356-422-7",pdfIsbn:"978-1-80356-424-1",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"f9f0fe8910dc02818cad71316650d297",bookSignature:"Prof. António Vieira",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11491.jpg",keywords:"Theory, Processes, Methodologies, GIS, Remote Sensing, UAV, Human Impact, Anthropocene, Slope Instability, Climate Change, Geomorphosites, Geotourism",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 25th 2022",dateEndSecondStepPublish:"April 27th 2022",dateEndThirdStepPublish:"June 26th 2022",dateEndFourthStepPublish:"September 14th 2022",dateEndFifthStepPublish:"November 13th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"A geographer with a career of more than 20 years devoted mainly to geomorphological research, centered in the topics of granitic geomorphology, soil erosion, and geomorphological heritage, and responsible for Ph.D. and Pos-doc researchers and for research project leadership. He is an assistant professor in the Department of Geography, University of Minho (UM), Portugal, and an integrated member of the Communication and Society Research Centre (CECS), UM.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"103627",title:"Prof.",name:"António",middleName:null,surname:"Vieira",slug:"antonio-vieira",fullName:"António Vieira",profilePictureURL:"https://mts.intechopen.com/storage/users/103627/images/system/103627.png",biography:"Antonio Vieira is a geographer with a Ph.D. in Geography from the University of Coimbra, Portugal (2009). He is an assistant professor in the Department of Geography, University of Minho (UM), Portugal, and an integrated member of the Communication and Society Research Centre (CECS), UM. He is a member of several scientific organizations, including the Portuguese Association of Geomorphologists (Chair from 2017 to 2019) and the Portuguese Association of Risk, Prevention and Security (vice-president since 2015). He is also a member of FuegoRED and coordinator of the FESP International Network. Dr. Vieira’s main research includes granitic geomorphology, geomorphological heritage and changes in land use, GIS and remote sensing, and their application to land use, geomorphological heritage, and soil erosion following forest fires and mitigation measures.",institutionString:"University of Minho",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"University of Minho",institutionURL:null,country:{name:"Portugal"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"10",title:"Earth and Planetary Sciences",slug:"earth-and-planetary-sciences"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"444318",firstName:"Nika",lastName:"Karamatic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/444318/images/20011_n.jpg",email:"nika@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Ehrlich’s early observations that water soluble dyes stained all organs of animals except for their brains and components of the central nervous system (CNS) was the key to our present day understanding of the BBB system. Subsequently, other researchers observed that dyes injected into the blood stream did not enter the brain hence a barrier existed between the two compartments [1].
\nThe BBB differs from normal membranes in that it possesses tight junctions between an endothelial cell/astrocyte wall with no pores to allow for transport unless materials are lipophilic, water, and/or an actively transported. The BBB is also lipophilic, free of aqueous electrolytes and highly electrical resistant. However, the BBB compartment can be traversed by lipophilic substances through passive diffusion, while other molecules that are substrates for transferases cross by direct transport [1, 2].
\nThe BBB prevents most systemic therapies from penetrating the brain; however, when cancer cells do penetrate the BBB from a peripheral origin, they generate neo-vascularization or cancer associated “vascular mimicry” structures (new blood vessels associated with tumor-generated penetrate breaks in the BBB) which can connect intracranial metastatic cancer cell colonies with the cerebral blood circulation [3]. If undesirable or toxic materials pass through the BBB into the CNS, a protective mechanism—the P-glycoprotein (P-gP) transfer system will transport toxic materials out of the CNS [4].
\nThus, developing new drugs that can exploit the cancer associated CNS “neo-angiogenic” vascularization that are not substrates for the P-gP system is of major interest and would be very useful in managing CNS and SNS malignancies.
\nFigure 1 shows a simplified diagram describing the BBB in relation to the brain (CNS) or spinal nervous system (SNS), the cerebral circulation and tumors growing in the CNS or SNS (Figure 2).
\nDepicts three modes of drug transport to primary and secondary brain cancer tumors
Describes breaks in the BBB and neoangiogenesis that can be initiated by both metastatic and primary cancers in the CNS, allowing RBCs with drugs to cross the BBB and penetrate the CNS and tumor masses (modified from Ref. [
Not all cancer cells infiltrate the CNS or SNS by breaching the BBB. A recent report by Yao et al. describes how acute lymphocytic leukemia (ALL) cells possess a6 integrin receptors that bind to laminin, a glycoprotein molecule that covers the surfaces of the meninges, its nerve sheaths and blood vessels [6]. Tiny blood vessels pass directly from the bone marrow through the vertebrae to the meninges tissue that line the spinal cord, brain and the cerebral spinal fluid (CSF) circulation. ALL cells can attach to the outside of blood vessels and nerves in the bone marrow and migrate over the scaffolding proteins. Thus, ALL cells can slide into the CNS and SNS via the scaffolding of the cerebral vascular circulation [6]. Other types of cancer may be able to do the same.
\nThe next step is to design new agents to block the a6 integrin receptor [6].
\nMost therapy regimens for CNS and SNS cancers involve empirical protocols [7]. However, with the advent of tumor targeted and gene mutation designed immunotherapies, there are more selective therapeutic approaches to the management of cancers [8].
\nHowever, if a tumor lacks a specific tumor target antigen, genetic mutation or receptor glycoprotein, then a more individualized (personalized) approach is possible. Through in vitro sensitivity studies, cytotoxicity parameters (IC50) vs. selected drugs can be identified for each individual tumor [9]. Obtaining tumor tissue for tumor molecular profiling can now be easily accomplished using liquid biopsy techniques and stem cell cultures [9, 13].
\nIn addition, since drugs penetrate the tumors in the CNS and SNS by lipophilic and/or selective transport mechanism(s), the partition coefficient,
The log
\n\n
The estimation of drug penetrating through the BBB (log BB) is the concentration of drug in the brain divided by concentration in the blood [11].
\nVery lipophilic compounds also tend to be highly protein bound. For a drug to diffuse from the plasma (at pH 7.4) across the BBB (log BB) into the CSF, the ideal octanol-water partition coefficient is usually 1–10 and corresponds to a log
In addition, when selecting a drug, the maximum concentration of drug in the plasma initially (Cmax) and the total drug concentration available after a single treatment—area under the curve (AUC), will be of assistance to predict if sufficient concentration of the drug is present [13].
\nThus, the combination of log
The above introductory information provides the general principles which govern the entry of anti-cancer cells
The medicinal chemists and molecular pathologists are constantly designing new agents for neuro-oncology. The goals are always the same—continue to develop new integrative drug designs vs. compliment specific receptors in the BBB or on vessels through which cancer cells penetrate the BBB.
\nMatthew Wood et al. claim that exosomes can cross the blood-brain barrier and deliver siRNAs, antisense oligonucleotides, chemotherapeutic agents and proteins specifically to cells—normal and malignant in the brain [15]. Exosomes are cell-derived matrix-bound encapsulated vesicles that contain drugs [15]. They are naturally or synthetically generated, able to cross the blood-brain barrier and deliver poorly solubilized drugs into the CNS and directly to brain cancer, as well as other diseases. Again, they must be able to pass the BBB.
\nNanoparticle drug delivery systems contain drugs bound to nanoparticles which are capable of traversing the blood-brain barrier [16]. Human serum albumin (HSA) is most widely used vehicle to design nanoparticles. The main benefits of HSA nanoparticles are that they are well tolerated with minimal side effects, as well as the albumin functional groups can be utilized for surface modification that allows for specific cell uptake. Nanoparticles have been shown to transverse the blood-brain barrier carrying host drugs into the brain [16]. To enhance the effectiveness of nanoparticles to cross the blood-brain barrier, attempts have been made to coat the nanoparticles with polysorbate to make them more permeable [16]. Polysorbate 80 coated nanoparticles containing doxorubicin delivered up to 6 μg/g concentrations of the drug into the brain after intravenous injections of 5 mg/kg of the drug/nanoparticles [16]. No detectable drug was observed when given alone or with the uncoated nanoparticles. This technology continues to have promise in neuro-oncology.
\nCNS prodrugs are derivatized forms of active drugs that are unable to cross the BBB. Designing active molecules that are derivatized with lipids, amino acids, esters, salts, etc., can improve the former molecules’ ability to penetrate the BBB more efficiently [14]. In situ in the CNS the prodrugs are metabolized or degenerated after crossing the BBB, releasing the active form of the drug [14].
\nThere are still major drawbacks to the use of prodrugs to treat tumors in the CNS. First, the prodrug may be able to pass through the BBB; however, it may be transported out of the CNS by the P-gP transport system without ever releasing the active drug. Second, the sheer size of these derivatized molecules makes it very difficult to pass through the BBB.
\nNevertheless, this is a very promising area for new research endeavors [14].
\nSimilar to the prodrug concept, another method to improve drug CNS bioavailability is through derivatizing drugs with peptides and amino acids that have select transfer pathways through the BBB and into the brain [17].
\nOne example is through the use of cholesterol [13]. Although the brain synthesizes its own cholesterol for support and metabolism, cholesteryl derivatized drugs behave like lipids and penetrate the BBB secondary to be lipophilic [13]. This type of masking works well and aids in traversing the blood-brain barrier. Also, a “target molecule” could be attached to the drug that helps it pass through the barrier and then once inside the brain released. If the drug is not transported out of the brain, then it is available for therapeutic use [13].
\nHowever, drawbacks to the above exist as well. Once the drug is in the brain there is a point where it needs to be degraded to prevent toxic changes in the brain tissue. Also the drug may not be transported out of the brain and could become toxic with increased concentration. There must always be a mechanism for the removal of the active form of the drug from the brain [13].
\nDrugs that increase the permeability of the BBB are described as receptor-mediated permeators (RMP) [18]. By decreasing the restrictiveness of the BBB, it is much easier for a molecule to pass through the barrier. RMPs increase the permeability of the blood-brain barrier temporarily by increasing the osmotic pressure in the blood which loosen the junctions between the endothelial cells and pericytes. By loosening the junctions, drugs can pass through the BBB and be available as therapy vs. cancer cells. These drugs must be administered in a very controlled environment because of the risk associated with their use [18].
\nFirst, a major concern is that the brain can be flooded with the drugs that are in the blood that are usually blocked by the BBB. Secondly, when the tight junctions loosen, the homeostasis of the brain can also be compromised, which can result in seizures and other dysfunctional events in the brain.
\nMicrobubbles are small “bubbles” of mono-lipids that are able to pass through the BBB. One obstacle to this, however is that these microbubbles are large, which often prevents their diffusion through the BBB and into the brain. This can be counteracted by focused ultrasound. Ultrasound increases the permeability of the BBB by causing interference in the tight junctions in the BBB. In combination with ultrasound therapy, a very specific area of diffusion will develop, because microbubbles can only diffuse where the ultrasound has disrupted the barrier [19, 20].
\nThe hypothesis and usefulness of this combination is the possibility of loading a microbubble with an active drug to diffuse through the barrier and target a specific area in the brain or spine. There are several important factors that make this a viable solution for drug delivery. The first is that the loaded microbubble must not be substantially greater than the unloaded bubble. This ensures that the diffusion will be similar and the ultrasound disruption will be sufficient to induce diffusion. A second factor is that the stability of the loaded micro-bubble must be stable. This means that the drug is fully retained in the bubble and there is no leakage.
\nLastly, it must be determined how the drug is to be released from the microbubble in the CNS once it passes through the BBB. Studies have documented the effectiveness of employing microbubble technology to get drugs to specific sites in the brain in animal models and humans [19, 20].
\nThe author hopes that the concepts discussed herein will be useful to stimulate research ideas that ultimately may lead to new treatments and approaches to the management of CNS and SNS tumors—primary and secondary.
\nThis review was supported by the following grants—NCI/SBIR grants—R43/44CA132257; R43CA203351; LACATS—U54 M104940-1.
\nVirus-induced cancers represent a huge burden, especially in developing countries. According to recent estimates from the International Agency for Research on Cancer (IARC), 16% of new cases of cancer worldwide are attributable to infections, of which 11% are viral infections. In sub-Saharan Africa, one-third of all cancers are infection-induced cancers [1]. Human papillomaviruses are small non-enveloped viruses (about 55 nm in diameter) of the Papillomaviridae family with a compact structure and a small circular genome (8000 base pairs), encoding 8–9 proteins depending on the genotype (LCR, L1, L2, E1, E2, E4, E5, E6, and E7) [2]. E5, E6, and E7 proteins are involved in cell proliferation and transformation [3, 4]. It is noteworthy that persistent infection with high oncogenic risk human papillomavirus (HR-HPV) can lead to precancerous lesions, which generally begin with slight modification (CIN 1), that can progress to more severe lesions such as CIN 2 then CIN 3 (carcinoma
In West Africa, the annual estimate of cervical cancer burden is 31,955 cases and 23,529 deaths [9]. However, most sexually active men and women can be infected with HR-HPV at some point in their lives, and persistent infection could lead to precancerous lesions and progress into invasive cancer [1, 5]. In addition, HPV infection can affect fertility in men [10, 11]. According to the World Health Organization (WHO), men genital infections with any type of HPV are estimated at least at 19.1% in sub-Saharan Africa [12].
In Burkina Faso, cervical cancer is the most commonly diagnosed cancer with an estimated incidence of 2517 cases and 2081 deaths per year [13]. In addition, otolaryngology and cervico-facial cancers are relatively frequent and account for 24.5% of this entity [14]. Gynecological cancers associated with persistent HR-HPV infection, therefore, threaten many African communities and economies, upsetting the trends of positive societal development. Although HR-HPV is the main causative agent of cervical cancer, other important cofactors (environmental or genetic) such as gene polymorphisms (E6, E7, MMP1, MMP3, TNF-alfa, and IL-18) are involved in the clearance and pathway of carcinogenesis [15].
HIV infection is an additional risk factor [16, 17] as well as some risky behaviors such as multiple sexual partners, especially among sex workers, leading to higher rates of cervical cancer [18] and increasing the risk of penile cancer in men [19]. Nevertheless, preventive measures through behavior modification, screening, and vaccination can significantly control these viral-induced cancers. To efficiently combat this pathology, it is, therefore, necessary to investigate whether the HR-HPV genotypes found in our populations, especially the most common in cancers cases, are covered by the available vaccines. To address this concern, the objective of the present study was to determine the distribution of HR-HPV genotypes in a general population including childbearing age women, teenage girls, HIV-infected women, women with high-grade precancerous lesions and invasive cervical cancer, sex workers, men, and histologically confirmed otolaryngology tumor (ear, nose, and throat) in Burkina Faso.
From 2013 to 2017, we carried out a large-scale, descriptive cross-sectional, and multicenter epidemiological study in Burkina Faso along with the retrospective data collection and analysis. The population of the present study consisted of 2386 participants, including eight (8) target groups: childbearing age women, teenage girls, HIV-infected women, sex workers, men, women with high-grade precancerous lesions (CIN 2/3), tissue from invasive cervical cancer, and histologically confirmed otolaryngology tumor (ear, nose, and throat cancers) in Burkina Faso.
The study was conducted in two phases: a descriptive cross-sectional study with 2025 participants made up of 1321 childbearing age women, 200 teenage girls, 183 HIV-infected women, 200 sex workers, and 124 men. We first focused on awareness-raising of HPV infection prevention and the risk of developing cervical cancer at several sites.
The goal after awareness-raising was to include in the target groups, all sexually active women (SAW) regardless of age who were not pregnant and provided informed consent to participate in the study. The exclusion was being in the menstruation period, during the study recruitment, and have had a total hysterectomy.
Prior to the samples collection, socio-demographic data, sexual behavior, HIV serology, level of knowledge about HPV and cervical cancer as well as associated diseases were collected using a standardized questionnaire. An individual collection card was used to collect clinical data of each sex worker in the study population. The privacy and confidentiality were respected through the generation of a unique code for each participant.
Midwives and gynecologists using a single-use speculum and sterile swab performed endocervical samples collection at the squamocolumnar junction. The following samples were taken:
from May 2009 to January 2010, 183 endocervical samples from women aged 20–53 years of age, who tested positive for anti-HIV antibodies at the stage of asymptomatic infection, were collected in three reference health centers accessible to all inhabitants of Ouagadougou [Saint Camille Hospital of Ouagadougou (HOSCO) and Pietro Annigoni Biomolecular Research Center (CERBA), two reference centers for people living with HIV/AIDS (PLWHIV), and Bogodogo University Hospital]. Participants were monitored at HOSCO and CERBA and were annually screened for cervical cancer.
from September to December 2013, 200 endocervical samples from teenage girls, aged 15–19, were collected in a youth health center (ABBF) of Ouagadougou. The participants were seen at gynecological consultation for voluntary HIV testing;
from December 2015 to September 2016, 124 sperm samples were collected in three medical clinics of Ouagadougou (Philadelphia, Sainte Elisabeth, and Sandof) after 3–6 days of abstinence according to the WHO recommendations. These male subjects aged 21–72 came for spermogram and spermocytogramanlyses;
from December 2015 to March 2017, 1321 endocervical samples from childbearing age women (15–76 years of age, general population), including 520 in Ouagadougou, 535 in the Hauts-Bassins region (Bobo and Orodara), and 266 in the Center-East region (Tenkodogo and Garango);
from June to August 2017, 200 endocervical samples from sex workers aged 16–50 years were enrolled in Ouagadougou.
The samples thus collected were frozen in a transport medium at −20°C except those from HIV+ women, which were stored at −80°C. The samples were then sent to the CERBA/LABIOGENE molecular biology and genetics laboratory for molecular biology analyzes. Following sampling in women, screening for precancerous lesions was performed using visual inspection of the cervix with acetic acid (VIA) or with Lugol’s iodine (VILI).
The second phase, a cross-sectional study with retrospective data collection, involved 358 samples. Using patients medical register available at the Department of Anatomy and Cytopathology of YalgadoOuedraogo University Hospital Center (CHU-YO), 118 cervical tissue specimens were selected based on high-grade (CIN 2/3) intraepithelial lesions diagnosis between February 2009 and May 2015 along with 112 cervical tissue specimens dated from 2009 to 2015 with a histological diagnosis of invasive cervical cancer.
According to the same protocol, we also included 128 histologically confirmed otolaryngology cancerous tissues dated from 2007 to 2017 in four health centers of Ouagadougou, CHU-YO, Shiphra, Sandof, and Philadelphia clinics. All these biopsy specimens were fixed in formalin and embedded in paraffin.
HR-HPV viral DNA was extracted using the DNA-Sorb-A kit (Sacace Biotechnologies, Como, Italy) from endocervical and sperm samples following the protocol provided by the manufacturer. Endocervical samples of HIV-positive women, DNA was extracted using bio solutions “INSTANT Virus DNA Kit” Analytkjena® (Italy). The extracted DNA was then quantified using UV spectrophotometry at 260 nm and stored at −20°C until PCR amplification.
In the cytopathology anatomy laboratory of the CHU-YO, the paraffin blocks containing a piece of biopsy were cut with a microtome to obtain five sections of about 20 μm thick. Tissues thus collected in sterile Eppendorf tubes were sent to the CERBA/LABIOGENE for molecular analyzes. DNA extraction was performed using the FFPE DNA Purification Kit, following the protocol provided by the manufacturer.
Each semen sample was assessed according to the following parameters: volume, motility, concentration, morphology, and vitality of spermatozoa, using an optical microscope.
Extracted DNA was amplified with “HPV Genotypes 14 Real-TM Quant” kit (Sacace Biotechnologies, Como, Italy) using Sacycler-96 Real-time PCR v.7.3 (SACACE Biotechnologies®). Fourteen HR-HPV genotypes (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) could be detected in a multiplex PCR procedure with β-globin gene as internal control.
Two different techniques were used to amplify the viral DNA extracted from samples of HIV+ women: PCR/Hybridization for the detection of HPV 6, 11, 16, 18, 45, 30’S and 50’S using the “HPV Blot STAR” kit from Diatech® (Italy), without discrimination of the HPV 30’S and 50’S genotypes, respectively. The second technique using the “HPV High-Risk Typing Real-TM” kit (SACACE biotechnologies®, Italy) allows specific detection of the following high-risk genotypes: 16, 18, 31, 39, 45, 59, 33, 35, 56, 51, 52, and 58. The amplification program was as follows: 1 cycle of 95°C for 15 minutes; 5 cycles of 95°C for 05 s, 60°C for 20s, 72°C for 15 s; 40 cycles of 95°C for 05 s, 60°C for 30s, and 72°C for 15 s.
Each phase of the present study received the approval of the Ethics Committee for Health Research of Burkina Faso (CERS) (n °2009-009/CR/135 of April 22, 2009 (HIV+); N2014-8-099 of August 6, 2014 (CIN2/3); Deliberation No. 2016-2102-0012 of 02/03/2016 (general population); No.2017-1026/MS/RCEN/DRSC (sex workers); No. 2014-8-099 (ICC); Ref.2017/CERBA/II-24/0019 of 24-02-2017 (otolaryngology samples) along with approbation of the regional health directorates (DRS) of the various target collection sites. Free and informed consent, anonymity, and confidentiality were strictly observed.
Statistical analysis of data was performed using IBM SPSS 21 and Epi Info v7.0 software. The Chi-square test was used for comparisons with a significant difference for
The present study focused on eight (8) target groups, including childbearing age women, adolescent girls, HIV-infected women, sex workers, men, high-grade precancerous lesions (CIN 2/3) cases, invasive cervical cancer, and histologically confirmed otolaryngology tumors in Burkina Faso. The mean age ranged from 18.7 ± 0.7 to 46.32 ± 12.76 years (Table 1).
Target groups | childbearing age women in the general population | Teenage girls | Sex workers | CIN 2/3 | ICC | HIV+ | Men | Otolaryngology cancers |
---|---|---|---|---|---|---|---|---|
Mean age (years) | 32.0 ± 10.1 | 18.7 ± 0.7 | 27.3 ± 0.4 | 41.5 ± 9.8 | 46.3 ± 12.8 | 33.9 ± 6.2 | 37.1 ± 7.6 | 41.0 ± 19.0 |
Range | 15–76 | 15–19 | 16–50 | 22–74 | 21–84 | 20–53 | 21–72 | 5–80 |
Mean age of target groups in the study population.
The general female population of the present study consisted of 1321 childbearing age women and 200 adolescent girls. Among them, only 142 (9.34%) had a university education while 951 (62.53%) were living with a partner. Most of them (61.34%) were over 18 years of age at first, and 43.19% never used a condom during sex. It is noteworthy that 40.89% of them had a history of STIs and 50.43% declared to be using contraception. Screening for precancerous lesions using VIA/VILI revealed 70 positive women (Table 2).
Characteristic | Target groups | |||
---|---|---|---|---|
Childbearing age women | Teenage girls | Women in the general population | ||
Educational level | Illiterate | 433 (32.78%) | 2 (1%) | 435 (28.6%) |
Primary | 293 (22.18%) | 58 (29%) | 351 (23.08%) | |
Secondary | 495 (37.47%) | 98 (49%) | 593 (38.98%) | |
University | 100 (7.57%) | 42 (21%) | 142 (9.34%) | |
Marital status | Married/cohabiting Single | 940 (71.16%) | 11 (5.5%) | 951 (62.53%) |
Widow | 325 (24.60%) | 189 (94.5%) | 514 (33.79%) | |
56 (4.24%) | 56 (3.68%) | |||
Age at first sexual intercourse | < 18 years | 452 (34.22%) | 102 (51%) | 554 (36.42%) |
≥ 18 years | 835 (63.21%) | 98 (49%) | 933 (61.34%) | |
No answer | 34 (2.57%) | 34 (2.24%) | ||
Condom use | Never | 633 (47.92%) | 24 (12%) | 657 (43.19%) |
Rarely | 263 (19.91%) | 102 (51%) | 365 (24%) | |
Always | 124 (9.39%) | 74 (37%) | 198 (13.02%) | |
No answer | 301 (22.78%) | 301 (19.79%) | ||
STIs history | Yes | 605 (45.80%) | 17 (8.5%) | 622 (40.89%) |
No | 716 (54.20%) | 183 (91.5%) | 899 (59.11%) | |
Use of means of contraception | Yes | 605 (45.80%) | 162 (81%) | 767 (50.43%) |
No | 716 (54.20%) | 38 (19%) | 754 (49.57%) | |
VIA/VILI+ | Positive | 58 (4.39%) | 12 (6%) | 70 (4.6%) |
Sociodemographic data and sexual behavior of the women general population.
The beta-globin gene used as an internal control was an essential factor for results validation in multiplex real-time PCR procedures for HR-HPV genotypes detection. Out of 118 CIN 2/3 tissue blocks samples, 43 positives for the beta-globin gene were considered valid while 65 samples were valid out of the 112 ICC specimens. Only valid samples were considered for the present study. HPV data were therefore available for 2264 valid samples out of 2386 recruited participants.
The prevalence of HR-HPV ranged from 15.63% to 72.31% based on the target population and nature of the samples. The overall prevalence was estimated at 39.05% (824/2264). As shown in Figure 1, a prevalence of 72.31% (
Prevalence of HR-HPV according to the target groups and nature of the samples in the study population.
The amplification kits used enabled us to essentially characterize the HR-HPV genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68. Table 3 shows the distribution of HR-HPV in descending order in the study population. Overall, varied distribution of HR-HPV genotypes was observed with predominance of non-HPV 16 and 18 genotypes (Table 3).
Target groups | Sample size | Prevalence of HR-HPV (CI 95%) | Most common HR-HPV | Absent genotypes |
---|---|---|---|---|
Childbearing age women in the general population | HPV 16 absent in hauts-bassins | |||
Teenage girls | ||||
Sex workers | ||||
HIV+ women | ||||
CIN 2/3 | HPV 16. 58. 66 | |||
ICC | HPV33; 66; 68 | |||
Otolaryngology cancers | HPV31;35;51;58;59; 66 and 68 | |||
Men | ||||
General population (women + men) | ||||
Target groups | ||||
Burkina Faso (Bilan) |
Genotypic distribution of HR-HPV in target groups.
NB: The general population consists of childbearing age women, adolescent girls, and men. The target population consists of sex workers, HIV+ women, CIN 2/3 cases, ICC cases, and otolaryngology cancers.
On the one hand, HPV 16 was particularly absent in childbearing age women from the Haut-Bassins region, in southwestern Burkina Faso, and in women with high-grade precancerous lesions (Table 3). On the other hand, HPV 18 was most common in ICC cases and HIV-positive women. In addition, HPV 56 was predominant in childbearing age women, otolaryngology cancers, and men. However, a predominance of HPV 68 was registered in sex workers and absent in ICC and otolaryngology cancers. It is noteworthy that HPV 56 was predominant in the general population as well as in the target groups (Table 3).
Table 4 shows the HR-HPV genotypes detected in the present study population and their prevalence in each target population. Considering the five most common HR-HPV genotypes found in the different target groups, HPV 16 presented a low proportion, especially in childbearing age women (1.82%), adolescent girls (5.2%), sex workers (2.7%), HIV + (4.9%), CIN 2/3 (0.0%). However, in decreasing order of frequency, it was the third genotype identified in otolaryngology cancers, the fourth in ICC, and the fifth in men. In HIV-positive women, a frequency of 2% of HPV6 infection was observed.
HR-HPV genotypes identified | HPV56 (7.60%) | HPV56 (7.80%) | HPV56 (8.70%) | HPV56 (1.43%) | HPV56 (45%) | 70.53% |
HPV18 (6.20%) | HPV18 (18.80%) | HPV18 (4.30%) | HPV18 (25.71%) | HPV18 (10%) | 65.01% | |
HPV39 (6.20%) | HPV39 (2.60%) | HPV39 (21.70%) | HPV39 (12.86%) | HPV39 (5%) | 48.36% | |
HPV45 (5.80%) | HPV45 (6.20%) | HPV45 (13%) | HPV45 (12.86%) | HPV45 (5%) | 42.86% | |
HPV31 (12%) | HPV31 (10.70%) | HPV31 (4.30%) | HPV31 (15.71%) | HPV31 (0%) | 42.71% | |
HPV35 (7.10%) | HPV35 (13.30%) | HPV35 (13%) | HPV35 (7.14%) | HPV35 (0%) | 40.54% | |
HPV33 (1.80%) | HPV33 (5.80%) | HPV33 (8.70%) | HPV33 (0%) | HPV33 (20%) | 36.30% | |
HPV52 (9.30%) | HPV52 (8.80%) | HPV52 (8.70%) | HPV52 (2.86%) | HPV52 (5%) | 34.66% | |
HPV16 (2.70%) | HPV16 (4.90%) | HPV16 (0%) | HPV16 (12.86%) | HPV16 (10%) | 30.46% | |
HPV51 (8.90%) | HPV51 (5.20%) | HPV51 (8.70%) | HPV51 (1.43%) | HPV51 (0%) | 24.23% | |
HPV58 (7.10%) | HPV58 (8.10%) | HPV58 (0%) | HPV58 (5.71%) | HPV58 (0%) | 20.91% | |
HPV68 (14.60%) | HPV68 (0%) | HPV68 (4.30%) | HPV68 (0%) | HPV68 (0%) | 18.90% | |
HPV59 (3.10%) | HPV59 (5.80%) | HPV59 (4.30%) | HPV59 (1.43%) | HPV59 (0%) | 14.63% | |
HPV66 (7.60%) | HPV66 (0%) | HPV66 (0%) | HPV66 (0%) | HPV66 (0%) | 7.60% | |
HR-HPV genotypes identified | HPV56 (15.94%) | HPV56 (8.80%) | HPV56 (20%) | 44.74% | ||
HPV52 (12.73%) | HPV52 (22.80%) | HPV52 (6%) | 41.53% | |||
HPV39 (8.25%) | HPV39 (13.20%) | HPV39 (11%) | 32.45% | |||
HPV59 (10.91%) | HPV59 (14%) | HPV59 (3%) | 27.91% | |||
HPV51 (7%) | HPV51 (10.30%) | HPV51 (6%) | 23.30% | |||
HPV35 (5.45%) | HPV35 (10.30%) | HPV35 (6%) | 21.75% | |||
HPV31 (3.36%) | HPV31 (3.60%) | HPV31 (11%) | 17.96% | |||
HPV18 (6.01%) | HPV18 (5.20%) | HPV18 (6%) | 17.21% | |||
HPV68 (5.17%) | HPV68 (0%) | HPV68 (11%) | 16.17% | |||
HPV16 (1.82%) | HPV16 (5.20%) | HPV16 (8%) | 15.02% | |||
HPV66 (11.05%) | HPV66 (0%) | HPV66 (3%) | 14.05% | |||
HPV58 (5.17%) | HPV58 (4.40%) | HPV58 (0%) | 9.57% | |||
HPV45 (5.03%) | HPV45 (1.50%) | HPV45 (3%) | 9.53% | |||
HPV33 (2.10%) | HPV33 (0.70%) | HPV33 (6%) | 8.80% |
Prevalence of HR-HPV in risk population, precancerous lesions, and cancer cases.
PCR screening in each target group revealed that among the 884 cases of HR-HPV infections, the number of genotypes per infected person ranged from 1 to 9 out of 14 genotypes tested. Single infection (isolated infection) ranged from 37.61 to 90.50% while multiple infection varied from 9.50 to 62.39% (Table 5).
Target groups | Presence of HR-HPV | Type of HR-HPV according to target groups | ||||
---|---|---|---|---|---|---|
HR-HPV − | HR-HPV+ | P-value | Single infections | Multiple infections | Number of HR-HPV genotypes per infected person | |
Childbearing age women n = 1321 | 64.57% (853/1321) | 35.40% (468/1321) | < 0.001 | 63.68% (298/468) | 36.32% (170/468) | 1–6 |
Teenage girls, | 58.5% (117/200) | 41.50% (83/200) | 0.001 | 57.80% (48/83) | 42.20% (35/83) | 1– 5 |
Sex workers, | 47% (94/200) | 53% (106/200) | 0.230 | 46.20% (49/106) | 53.80% (57/106) | 1–9 |
HIV+, | 36.06% (66/183) | 63.90% (117/183) | < 0.001 | 37.61% (44/117) | 62.39% (73/117) | 1–7 |
CIN 2/3, | 51.16% (22/43) | 48.80% (21/43) | 0.829 | 90.50% (19/21) | 9.50% (2/21) | 1–2 |
ICC, | 27.69% (18/65) | 72.31% (47/65) | < 0.001 | 65.96% (31/47) | 34.04% (16/47) | 1–4 |
Otolaryngology cancers, | 84.37% (1O8/128) | 15.63% (20/128) | 0.722 | 90% (18/20) | 10% (2/20) | 1–2 |
Men, | 82.26% (102/124) | 17.74% (22/124) | < 0.001 | — | — | — |
Total, | 60.95% (1380/2264) | 39.05% (884/2264) | <0.001 |
Prevalence of single and multiple infections in target groups.
The HR-HPV genotypes targeted by bivalent/quadrivalent HPV vaccines (HPV6/11/16/18) were identified in 7.83% of childbearing age women, 10.40% of adolescent girls, 8.90% of sex workers, 25.70% of HIV+ women, 4.30% of CIN 2/3, 38.57% of ICC cases, 14% of men, and 50% of otolaryngology cancer cases. The genotypes covered by the nonavalent vaccine (HPV6/11/16/18/31/33/45/52/58) were 36.22, 43.40, 44.90, 65.30, 39, 75.71, and 40%, respectively in childbearing age women, adolescent girls, sex workers, HIV-positive women, CIN 2/3, ICC, men, and otolaryngology cancer. HR-HPV not covered by bivalent, quadrivalent, or nonavalent HPV vaccines were observed with a higher prevalence in childbearing age women (63.18%), CIN 2/3 cases (61%), and men (60%) (Figure 2).
Prevalence of HR-HPV identified in the target groups of our study according to their coverage by available vaccines.
HPV is one of the carcinogenic viruses, sexually transmitted, widespread in the world with a high prevalence in developing countries especially in Sub-Saharan Africa where socio-cultural and behavioral factors which promote transmission prevail in several regions. In the present epidemiological study, including 2386 samples out of which 2264 were valid using the PCR technique, the overall prevalence of HR-HPV was 39.05% (824/2264). This prevalence is in line with those reported in previous studies supporting a global prevalence of 10.4% of HR-HPV infection [20] which can reach 36.5% in some developing countries [21, 22].
Epidemiological studies suggested a difference in the prevalence and distribution of HR-HPV genotypes in infected women according to regions and risk groups throughout the world [23, 24] Our results support this variable prevalence and distribution of HR-HPV according to target populations and sample types.
Indeed, the prevalence of 35.40% of infection observed in the population of childbearing age women was lower than that reported in some studies from Tanzania (74%) [25] and Ethiopia (83.2%) [26]almost similar to that of a study conducted in England (35%) [27].
HR-HPV is the main etiologic agent responsible for ano-genital cancers including ICC and a prevalence of 100% could be expected in ICC cases. The high prevalence of 72.31% of HR-HPV infection in ICC cases found in this study was lower than the 100% reported in Gabon [28], 90,7% in Nigeria [29], and 83,2% in Malaysia [30]. The difference in the methodologies used could support the existence of false-negative samples as reported in a previous study by Tan et al. [30] in Malaysia.
Furthermore, sex workers and men, an important active group for the maintenance of HPV in the population, showed a high prevalence of HR-HPV in our study. For instance, some studies reported a significant association between HPV infection, high number of sexual partners, and history of STIs [31]. The prevalence of 53% found among sex workers in our study was higher than those of 51.5% and 26% reported respectively in Côte d’Ivoire [32] and Ghana [7]. In contrast, the infection rate of 17.74% in the men of our study population was lower than the 32.4% observed by Zhu et al. [33] in men with genital warts. These results support the fact that sex workers and men constitute a reservoir for the transmission of HR-HPV, hence the importance of awareness-raising among these risk populations about the screening for HPV infection.
Data analysis also showed that 48.80% (21/43) of women with high-grade precancerous lesions (CIN2/3) were infected with HR-HPV; a lower prevalence than the 91.9% reported in another study in a similar population [34]. These results could be explained by the higher rate of infection in women under 30 years old, especially in those of 25–29 and 60 years and over [35, 36, 37]. For instance, the mean age of women with CIN 2/3 in our study was 41.5 ± 9.8 years (22–74 years) against was 45.7 years in the study of Wang et al. (21–83 years old).
Several studies reported a high prevalence of HPV infection in HIV+ women [7, 38] as HIV is a well-known factor associated with an increased risk of HR-HPV persistence and multiple infections, and therefore, promote the occurrence of anogenital cancers. The prevalence of 63.90% of HR-HPV observed in this target group of the present study was similar to 65.5% in Ghana [39] but higher than the 36% reported in Nigeria [40] and 33.3% in Brazil [41]. Compared to non-HIV infected women in the general population, this high prevalence could be explained by the immunosuppression and confirm the role of HIV infection as an additional risk factor for the persistence of HR-HPV.
The infection rate of 41.5% found in adolescent girls was lower than the 66.7% observed in South Africa [32]. The difference in age range (15 to 19 years in our study versus 16 to 22 in the South African study) could explain the prevalence variation between the two studies especially when previous studies support that HR-HPV infection is higher in those less than 30 years of age [37].
In our study, HPV 56 was the most common genotype in childbearing age women, men, and otolaryngology cancers with predominance in the general population as well as target groups. This genotype is not covered by any available HPV vaccine, although it has been found in ICC and CIN 2/3 cases [29]. The same is true for HPV 68 which was the most common genotype in sex workers and the fourth common in men.
Since sexual transmission is possible between men and women, the presence of these genotypes in ICC and CIN 2/3 cases suggests a low clearance of the latter HR-HPV genotype in Burkina Faso.
HPV 18 was more common in HIV-positive women and ICC cases with a high frequency of 18.8 and 25.71% respectively. It was also present in CIN 2/3 up to 4.3 and 10% in otolaryngology cancers. Our results are in line with those of studies reporting that this persistent genotype is one of the most commonly found in cervical cancers [29].
Immunodeficiency of HIV-infected women coinfected with HPV 18 promotes high-grade precancerous lesions and the occurrence of invasive cancer of the cervix. It would therefore be necessary to strengthen surveillance through screening, treatment, and vaccination of HIV-infected women.
In addition, unlike studies reporting HPV 16 as the most common genotype throughout the world, especially in cervical cancers [13, 28, 30, 42, 43], this genotype was classified among the less frequent HPVs in our study. However, in ICC (12.86%), otolaryngology cancers (10%), and in men (8%), HPV 16 was not one of the most common genotypes but reached a frequency that required attention. The low prevalence of HPV-16/18 in our 2386 samples remains an enigma to be elucidated. It remains true that not only the distribution of the HPV genotypes would vary according to the continents, the zones, the countries, and the target populations but also the clearance and the borrowing of the pathway of the carcinogenesis induced by these viruses is modulated by genetic polymorphisms of their human hosts. [44, 45]. Evidence from the literature support that the HPV16/18/31/33/35/45/52/58 genotypes are the most common genotypes found in 20% of cervical cancer cases worldwide [24].
The results of the present study also revealed a high prevalence of HR-HPV genotypes covered by the nonavalent vaccine (36.22–75.71%) as well as genotypes of HPV not covered by the vaccine (24.29–63,18%). It is noteworthy that some of the genotypes not covered by vaccine were found in high-grade precancerous lesions and cervical cancer cases [29, 46].
For effective prophylactic actions to control HPV infection, the present epidemiological study in Burkina Faso shows variable distribution of HR-HPV genotypes in the different target populations. Our results suggest that implementation of the nonavalent vaccine is important for HR-HPV infection control in Burkina Faso. Promotion of screening of men, especially for penile cancer and genital warts, and young boys vaccination programs are required since men are well-known reservoirs for HR-HPV dissemination.
The studies carried out in Burkina Faso show the circulation of fourteen high-risk HPV genotypes among different layers of the population. The prevalence of HPV infection and genotypes distribution varied among target groups with an overall predominance of non-HPV 16 and 18 genotypes. Moreover, the high-risk HPV genotypes found in Burkina Faso are not all covered by the available vaccines. It is however crucial and important to focus on vaccination using available and accessible vaccines for developing countries to reduce the disease incidence. Cervical cancer and other HPV-induced cancers remain a global public health concern. Strengthening the implementation of primary, secondary, and tertiary prevention strategies incorporating information-education-communication and awareness-raising, will allow effective control of HPV infection and its consequences in men and women.
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