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HUMAN PAPILLOMAVIRUS (HPV)

What is a virus?

Louis Pasteur and his team were the first to observe that microorganisms even smaller than bacteria were able to cause diseases in animals and humans. Their writings on the rabies virus, in 1880, traced the path of a long and intensive period of research into viruses. At this time, microscopes were not sufficiently powerful to see such small microorganisms so, to study the effects of viruses, infected tissue was immersed in a solution which was then passed through a filter so that the very fine mesh would, in theory, trap and retain the cells or bacteria from the infected tissue. The filtered solution was then injected in an animal and it subsequently developed the disease. The filtered liquid contained a smaller microorganism than cells and bacteria, but this agent responsible for the animal´s infection was not yet identified. In 1935, the American scientist, Wendell Stanley, observed that if the solution was transferred to crystals and they were then, in turn, dissolved, this still caused disease. This suggested that denatured viruses could continue to be pathogenic, via their proteins. Subsequently, it was shown that viruses contain genetic material, DNA (deoxyribonucleic acid) or RNA (ribonucleic acid), which are substances found in the nucleus of a cell.

The specific proteins of each type of virus generate changes in the cell which cause disease, so each type of virus has a tissue specificity. Thus, the influenza virus will lodge in the bronchial cells, the hepatitis virus in the cells of the liver and the genital papillomavirus in the linings of the cervix, vagina, vulva, perineum and anus. Other types of papillomavirus settle on the skin or in the oral cavity. Although they belong to the same family, the 200 types of papillomavirus recorded to date can be divided into groups which favour different sites.The specific proteins of each type of virus generate changes in the cell which cause disease, so each type of virus has a tissue specificity. Thus, the influenza virus will lodge in the bronchial cells, the hepatitis virus in the cells of the liver and the genital papillomavirus in the linings of the cervix, vagina, vulva, perineum and anus. Other types of papillomavirus settle on the skin or in the oral cavity. Although they belong to the same family, the 200 types of papillomavirus recorded to date can be divided into groups which favour different sites.

Viruses use their genetic material to take control of the infected cell, thus disrupting its function. They use the host cell´s machinery to reproduce themselves. Some viruses however penetrate the cell and can remain there dormant and latent, not causing any symptoms: this is the case with papillomavirus. So, viruses cannot exist without their host cells; this differentiates them from bacteria, which are self-sufficient.

In the face of these viruses and the proteins they produce, the organism will defend itself by producing antibodies* to neutralise the viral proteins. Natural immunity kicks in after a variable length of time to check and avoid disease.

Viruses and cancer

When research started, scientists observed the effects of viruses as the causal agents of infectious diseases. In 1911, another Frenchman, Roux, showed that the injection of a filtered “infected” solution could cause cancer in a bird. This marked the start of a long period of research.

Examples of cancers caused by viruses started to be observed. A virus was identified as being responsible for leukaemia in the cat, skin cancer in the rabbit and breast cancer in the mouse. The list is long and still growing. In man, this concept was quickly confirmed for certain tumours. This is the case with a lymphoma or cancer of the lymph nodes, called Burkitt´s lymphoma, caused by a virus called the Epstein-Barr virus, and the hepatitis B virus responsible for cancer of the liver.

Once the epidemiological data had implicated a sexually-transmissible agent, it then seemed obvious to look for a viral cause to cervical cancer. What was needed above all was proof that, if there were a virus, it was not a simple, temporary spectator but an actual actor in this process. To use an analogy, that it is not a witness to a crime but the perpetrator.

History

In 1907, it was shown that genital warts can be transmitted by a solution of crushed infected tissue, pointing to transmission by an infectious agent. In 1933, researchers demonstrated that the virus responsible for genital warts caused skin cancer in the rabbit. However, it was already apparent that these viruses were not always solely responsible for the rabbit´s cancer, but that something else was needed to “help” them, for example a certain food or over-exposure to sunlight.

It was in the period from 1960 to 1970 that epidemiological data showed that the disease was transmitted by sexual contact and this discovery inspired the search for a microbial agent. Indeed, in 1960, Papanicolaou observed cells from abnormal lesions suspected of causing cervical cancer. At this time, the herpes virus was thought to be responsible: however, the indirect connection with cervical cancer was not demonstrated.

In the 1970s, researchers proved that the genital wart viruses infecting cells were not of a single type, and their different DNAs led to the identification of several types of virus. They all belonged to this same group but caused different phenomena. Some were responsible for warts on the skin and others for lesions on the cervix, the vagina, the vulva and the anus. But they all affected just one type of tissue, the malpighian or squamous epithelial lining which covers the surface of the cervix, the genital mucous membranes and the skin.

In 1975, the virologist Harald zur Hausen demonstrated, for the first time, that HPV was a virus transmitted by contact, i.e. touch or sexual relations, and he counted various types of human papillomavirus.

In the 1980s, numerous studies worldwide identified the very large number of HPV strains, describing their specificity and their pathogenic power (capacity to generate a disease), and likewise their role in the genesis of cervical cancer. Other less harmful HPV strains could cause benign lesions such as warts, condylomata or papillomas.

With technological developments in research, it was possible to classify these viruses according to the sites where they act in the tissue. Close to 200 viral strains have today been identified on the basis of their DNA sequence, and their number is still growing. About forty have a possible impact on the ano-genital mucous membranes (cervix, vagina, vulva, anus), and on the skin, vulva, perineum and the anal area. The region most frequently affected, as it is the most vulnerable, is the cervix.

Type 1 for example is responsible for warts on the skin. The warts observed in the genital area, such as the penis or vulva, are usually caused by types 6 and 11. Types 16 and 18 are most frequently found in severe dysplasia and cervical cancer.

Very quickly, it was possible to classify the papillomavirus types into two distinct categories:

• so-called low-risk papillomavirus strains, which are never found in cancers and pre-cancers: this is the case with types 6 and 11, responsible for genital warts, also called condyloma acuminata;

• so-called high-risk papillomavirus strains, which are found in pre-cancerous lesions (CIN2/3) and cancerous lesions of the cervix, vagina, vulva and anus. It is important to remember here that the term “high-risk” does not mean an inevitable development into cancer. The risk affects women who persistently ignore the infection or its benign consequences on the cells. This is, of course, rarely the case in our countries since screening is widespread.

Common to both categories of virus is the fact that they are transmitted by sexual contact and that they penetrate the cell and develop there. They then cause changes to it, testifying to their replication in the cell nucleus. However, one of the fundamental differences between these two categories is that the low-risk strains, when they penetrate the cell, cause a benign proliferation of the cells, causing warts, but these viral strains cannot transform the cell and cannot integrate the DNA of certain chromosomes of the nucleus of the infected cell: the process of cell proliferation caused by these viruses always remains benign. In contrast, high-risk papillomavirus strains can disrupt the division of the infected cell, incorporate themselves in the DNA of the infected cells and thereby disrupt their normal division: this is the process of dysplasia, where the now unstable cell develops first into a pre-cancer and then eventually into a cancer.

Where the virus is detected in cell samples, the cervix and the vagina are found to be exposed more often to high-risk papillomavirus types than to low-risk ones. This is why condyloma acuminata tends to be observed on external sites, whereas dysplasia more frequently affects the cervix. However, condyloma acuminata and dysplasia can coexist on all sites.

In 1995, the IARC (International Agency for Research on Cancer) classed HPV 16 and 18 as carcinogenic agents (responsible for cancer) in humans. For over twenty years, real progress has been made in the understanding of HPV infections responsible not only for cervical cancer but for other pathologies too.

Since 1988, EUROGIN (European Research Organisation on Genital Infection and Neoplasia) has coordinated and conducted research in Europe and throughout the world on HPV infection. In collaboration with the World Health Organization (WHO), EUROGIN has hosted expert consensus conferences to promote a series of recommendations on strategies for controlling and preventing cervical cancer. Being a major player in research, and as it coordinates and diffuses research results via numerous international publications and conferences, EUROGIN plays an active role throughout the world and France (via PROGIN) in the education and training of professionals (www.eurogin.com).

Impact of the papillomavirus on the cells of the cervix

Low-risk and high-risk papillomavirus types can all penetrate the exposed cell. There they find the necessary ingredients for their division and development. They then replicate on the surface of the epithelium. This intense virus production in the cell leads to its change and death. This particular cell, characteristic of papillomavirus infection, is called a koilocyte.

The smear therefore enables these cells to be detected and their discovery means that the infection is present. This cell is found with both categories of infection and therefore does not allow high-risk lesions to be differentiated from low-risk lesions. To identify them, I would like to remind you of two things: on the one hand, the detection of the viruses themselves, by what is still called the HPV test, has allowed us to observe that the majority of viruses present on the cervix are high-risk HPV types, and that more than 80% of cervical lesions are caused by high-risk papillomavirus strains. On the other hand, as the lesion gets worse, it changes from the stage of infection to that of dysplasia of various grades. In this process, a reduction is observed in the effect of the viruses on the cells, and thus in koilocytes, in favour of dysplastic cells, the characteristics of which allow them to be classified as mild, moderate and severe dysplasia. Thus, in mild dysplasia, a few koilocytes are observed whereas in severe dysplasia, they no longer exist . However, it must be said that sometimes lesions of different stages can co-exist.

Where the smear reveals this type of abnormality, colposcopy is required to visualise any possible lesion. If there is one, a tissue sample is taken from the abnormal zone (biopsy). The microscopic analysis of this tissue will confirm the diagnosis of a pure viral lesion where there are numerous koilocytes on the surface of the epithelium. This lesion is called flat condyloma and is due to the presence of high-risk papillomavirus strains in over 65% of cases. However, depending on the age of the patient, it can regress spontaneously or be eliminated by the individual´s own immune system, something which occurs within two years in 50% of cases. Where the virus interferes with the host cell´s division process, the cell´s nucleus becomes enlarged and more dense: this is dysplasia. Dysplasia is mild (CIN1) where this process affects the lower third of the epithelium, moderate (CIN2) for the lower two-thirds, and severe (CIN3) for the entire epithelium.

CIN1 is defined as heterogeneous abnormalities characterised by multi-type HPV infection in around 40% of cases, where the presence of HPV 16 is less than 20%; it regresses spontaneously in 50% of cases and this is why it is not really a high-risk lesion. CIN2 and 3 form a more homogeneous group of lesions where HPV 16 and 18 are present in 65% of cases: they actually regress in less than 15% of cases and are considered high-risk lesions that always require treatment.

While certain types of so-called high-risk or oncogenic papillomavirus are considered risk factors for cervical cancer, the majority of women exposed to these viruses get rid of them spontaneously. It is estimated that just 20% of young women exposed to the virus will not manage to eliminate it in this way and will keep it persistently. Thus, 5% of them can, if not screened, go on to develop cancer. Screening thus gives women an additional chance to detect the infection early and to determine whether they are at risk of cervical cancer. By treating high-risk lesions appropriately, this cancer can now increasingly be prevented.

It has been demonstrated that condyloma virus strains are responsible for dysplasia and cancer of the cervix.

Electron-microscopy has helped progress to be made in the field of virology. Papillomaviruses belong to the papovavirus group. This word is in fact an acronym comprising the first two letters of the names of the oncogenic viruses of the papillomavirus groups of humans, the rabbit and the dog, and the polyomavirus of the mouse.

HPV (human papillomavirus) are very common DNA viruses which affect the skin and certain mucous membranes. They are small (from 45 to 55 nm in diameter). Their DNA is enveloped in a shell of viral proteins called the capsid. When the virus replicates in the cell, it still has its shell, and if dysplasia progresses, the virus loses it, becomes immature and will gradually integrate the genetic material (DNA of the chromosomes) of the cell and disrupt its division.

Exposure to viruses

Above all, it is important to understand that when we speak of HPV infection, this means the presence of the virus but not necessarily a lesion caused by the virus. I always explain that in the event of a ´flu epidemic, everyone breathes the ´flu virus but not everyone catches the disease “influenza”. Only a smear followed by colposcopy and biopsy will confirm or rule out the existence of a lesion caused by the virus.

80% of sexually-active subjects will be exposed to HPV at least once during their lifetime, but only 10% will fail to eliminate it spontaneously.

Papillomavirus is transmitted in most cases by sexual contact. It is one of the most common genital infections. Anyone who is sexually active can be exposed to the virus, both women and men, heterosexuals and homosexuals.

Studies conducted in a number of countries show that the worldwide average frequency of this infection stands at 10%, regardless of age. For high-risk HPVs, the frequency is estimated at 15% in France.

Prior exposure to HPV does not always guarantee protection against subsequent infection, as is the case for many other infectious diseases.

All sexually active women can be exposed to HPV. A single encounter is all that is needed, but clearly the risk increases with sexual activity and number of partners. The period of initial sexual contact is a particularly vulnerable time. Up to 40% of sexually-active young women may carry the virus, which in most cases, remains inactive or “dormant”, i.e. does not cause any lesions. This high frequency is due to the lack of preparation of the immune system which encounters these viruses for the first time, the higher number of sexual partners during this period, and the particular vulnerability of the transformation zone of the cervix at this young age. It is estimated that 80% of young women exposed to the virus will eliminate it spontaneously during the 18 to 36 months following contamination. These women will never know that they have been exposed to HPV unless they are systematically tested for HPV in the laboratory, which is unnecessary given the high level of spontaneous regression.

However, while the risk of exposure is high in the under 25s, it nonetheless continues throughout an individual´s lifetime, albeit with a lower probability. After the age of 30, the average frequency of the infection is 10%. After the menopause, however, in some studies, a slight increase in the frequency of the infection has been observed, probably due to a reduction in natural immunity at this age.

HPV infection is transmitted essentially by sexual contact

The risk of infection is higher in sexually-active young women, but persists throughout their entire sex life.

The most frequent mode of transmission is direct skin-to-skin contact during sex.

The transformation zone of the cervix is the most vulnerable site due to possible contact with the cells receptive to these viruses, i.e. the so-called basal cells, i.e. the deepest ones in the epithelial lining.

Vaginal penetration is not always necessary for exposure to the virus. HPV can be present, but dormant, on the skin and external mucous membranes, and can be transmitted by simple contact during touching or foreplay, without penetration.

Where a condom is used during penetration, the condom will protect the wearer but not always the partner. It can move the dormant virus from the outside towards the cervix.

However, it has been proved that where a condom is systematically used before sex, there is a significant reduction in infection compared with women who use a condom occasionally.

Sex facilitates contamination due to micro-trauma of the skin and the mucous membranes.

• For condyloma acuminata

Highly transmissible: the condom will protect the man but could move the virus from the outside towards the vagina or the cervix. If the lesions have not developed very much, this risk is low, but it is higher if the condylomata are more widely distributed. In any event, during sex, a condom must be worn. Examination of the male partner is strongly recommended.

These abnormalities are always benign and do not constitute a cancer risk. They are caused by so-called low-risk papillomavirus types (five types currently belong to this sub-group). The sites most often affected are the vulva, the perineum, the anus and, more rarely, the cervix and the vagina. The coexistence of condyloma acuminata and dysplasia is possible in certain situations. If the woman or the man is a carrier of condyloma acuminata, large quantities of virus are present in these lesions, that often occupy a large area. In this case, this is a real sexually-transmitted disease. The male partner of a woman with genital condyloma acuminata has an approximately 50% risk of having lesions of the same kind on his penis.

Genital condyloma acuminata is highly transmissible. The virus is usually transmitted by sexual contact, but sometimes also by simple contact with objects or a contaminated surface (towels in a bathroom etc.).

They may also be spread by self-transmission, i.e. from digital warts during touching (masturbation) or intimate washing. It is important to stress that condoms do not provide complete protection. Young people (15 - 25 years of age) are the target of choice for the development of these lesions.

Condyloma acuminata affects young men and women equally. Unlike high-risk papillomavirus lesions of the cervix, the time it takes for external genital condyloma acuminata to appear after exposure to the virus is eight weeks to eight months. However, after contact on one or more occasions, acuminate lesions do not systematically appear in the partner if her immune defence allows her to eliminate the virus. Moreover, genital condylomata can develop [disappear? regress?] spontaneously: those on the skin of the genital sphere and the vagina can disappear spontaneously - 35% of cases in 6 months, 53% in one year, 67% in 2 years; those on the cervix, for their part, regress in 50% of cases, stabilise in 40% and worsen in only 10% of cases.

Transmission occurs, very rarely, to babies born to mothers suffering from genital condyloma at the time of childbirth. The baby can be afflicted on the anus or genitals, or even the larynx and respiratory tract.

The papillomavirus strains which cause plantar warts cannot be transmitted to the genital organs.


• For dysplasia

Poorly transmissible from woman to man: for the reasons previously mentioned, the current male partner, although he could have transmitted the virus (which is by no means certain, as it could have been the previous partner), does not necessarily develop any disease, often getting rid of the virus spontaneously. A man without a visible lesion is generally unlikely to contaminate his partner. The male partner does not have to be examined. If the partner has genital lesions due to HPV, this does not prove that reoccurrences in the treated woman are linked to the untreated partner. It is true, however, that in this situation examining the partner can reassure the couple. Regarded in this way, high-risk HPV infection is not a sexually-transmitted disease like others. For all these reasons, and from the practical viewpoint, we largely play down the man´s role with regard to contamination when a woman presents with dysplasia of any grade. Therefore, a condom does not have to be worn and will not have any impact on possible recurrences, once the woman has been treated.

High-risk HPV situations after exposure

Three situations can arise following exposure to the virus.

• So-called latent HPV infection

The virus has penetrated the cell but is inactive.
This is where an individual is healthy but carries the virus, which is present in the mucous membranes or the skin without any visible abnormality or lesion.

In this case, the infection is described as latent or inactive. The virus can remain dormant - sleeping, so to speak - for months or years without any abnormality developing. In the vast majority of cases, the natural immunity which builds up following this infection, enables the virus to be eliminated spontaneously: this spontaneous elimination of the virus is called clearance and occurs generally in a period of 7 to 12 months. It is estimated that 80% of subjects exposed to the virus will have eliminated it naturally within a 36-month period. During this time, a dormant virus will not multiply. The latent infection is thus not contagious. The majority of individuals affected by this latent infection are not even aware they have it as it does not cause any visible abnormalities or symptoms.


• The persistent infection

If someone, for reasons specific to her, does not have a sufficient immune response to eliminate this virus, she develops a “persistent” infection. The persistence of the virus in the mucous membranes, in particular of the cervix, causes cell abnormalities, especially in a special, vulnerable area called the transformation zone. Persistence is the risk marker for dysplasia. This situation always precedes type CIN3 pre-cancerous lesions.


• The active infection

After a number of months of exposure to the virus, the infected cells undergo changes which are detected by smears. At this stage, the virus replicates on the surface of the epithelium: this is condyloma. But it can also become incorporated into the genetic material of the cell and disrupt its division: this is dysplasia. The lesions can be detected by examination of the cervix under the microscope (colposcopy). They appear in the form of “marks” from which samples can then be taken (biopsies). These “marks”, which are always benign and still called dysplasia or CIN (cervical intraepithelial neoplasia), are classified as grade 1, 2 or 3 depending on the severity of the cell changes. These lesions are considered, to various degrees, as benign abnormalities with a cancer risk. Undetected, they can form the site of cervical cancer over a relatively long period. All pre-cancerous lesions of the cervix are associated with the group of so-called high-risk papillomavirus types.

Remember that the site in the genital area most often affected by cancer, is the cervix due to the vulnerability of the transformation zone to high-risk papillomavirus strains.

Prognostic indicators of high-risk HPV infection

A number of factors are considered prognostic factors for the development of high-grade CIN.

• Age

Today, we have proof that the risk of an association between the persistence of HPV infection and the development of CIN is strongly correlated with age. Women over 35 years of age have reduced immunity to these viruses. Although the frequency of HPV infection is higher in young people under 25 years, this group have better immunity and so can eliminate the virus spontaneously in around 80% of cases. The spontaneous elimination of HPV is good and persistence is weaker up to 25 years of age. This indicates that this population is less at risk of CIN3 and cancer. Conversely, in older women, natural elimination decreases and persistence increases, meaning that this population is more at risk.


• Viral persistence

Persistence of HPV infection is a powerful indicator of current or future pre-cancerous lesions. It is generally accepted that persistence starts from an average time of 18 months, but there is no consensus about the exact definition of persistence and at what precise moment it starts. However, it falls gradually over time. At 6 months, it can reach 50%, whereas at 2 years it is just 20%.

Persistence increases with age. The risk of developing a high-grade lesion is correlated with the persistence of high-risk HPV infection while regression is associated with the absence of high-risk HPV. The high persistence of CIN in women who are sero-positive to HIV would thus be explained by a high rate of persistence of high-risk HPV infection compared with women who are sero-negative to HIV. Viral persistence always precedes the appearance of lesions.


• Viral type


Not all high-risk HPV strains have the same natural history and development, and immunity varies depending on the viruses present. On the other hand, persistence must relate to the same virus and not presence of all high-risk HPVs.

With increasing age, there is a reduction in the natural elimination of type 16 - the most active virus. Persistence of identical high-risk HPV types, and particularly of type 16, thus represents the greatest risk for the development of CIN3. This risk is estimated at 20% over a period of ten years following exposure.


• Viral load

This is the quantity of virus present in a lesion. Routine techniques do not permit this load to be measured precisely, without PCR. But simple new techniques are now available which are able to measure it. The high viral load enables a normal cervix to be distinguished from a cervix with a CIN. In this context, it forms a lesional marker. However, it does not make any distinction between the various CIN types. Thus, a CIN1 can have a low load and a CIN3 a high load and conversely. This is largely due to the fact that the lesions are heterogeneous: condylomata, virus-producing lesions and high-grade CINs which produce little virus can all develop on the cervix at the same time.

Factors which influence viral persistence

I would like to stress two things. On the one hand, the risk factors that are independent of viruses can interfere with it, but are not powerful factors. In other words, this means that they do not have a significant effect on the development of the disease compared with HPV itself. Their risk level for cervical cancer ranges from 1.5 to 3, while HPV has a risk level 10 to 15 times higher.

Moreover, effective and successful prevention of cervical cancer relies not on action against these factors but rather on the early detection and treatment of pre-cancerous lesions.

While numerous factors can influence viral infection, making it difficult to carry out comprehensive studies, a number of leads have been explored. Firstly, the cervix is indisputably subject to the influence of sex hormones: oestrogens and progestogens definitely have an effect. Taking the Pill for more than ten years is nonetheless a low risk factor. Among the other risk factors, it must be stressed that CINs and cancer of the cervix are mainly found in women who smoke. To explain this phenomenon, it can be hypothesised that smoking has an impact on the micro-circulation, in other words on the vascular system of the cervix, resulting in a chronic congested state. The carcinogenic effect of tobacco has also been considered, and likewise its local immuno-suppressant action. As has been frequently reported for other types of cancer, the risk of developing cervical cancer increases in line with the quantity the woman smokes and the number of years she has been smoking. Pregnancy is also a period which favours the emergence of viral dysplasia. The strong influx of hormones which occurs and the lowered immunity are without doubt the two main reasons for this finding. The cervix becomes more vulnerable to the action of HPV viruses and their replication is easier. However, it is important to remember that pregnancy is only a high-risk situation if the HPV virus is already present, as pregnancy then favours the emergence of viruses which already exist - but it is not a risk situation per se if there has not been any prior exposure. Likewise, immune suppression is also a risk factor. Numerous studies have mentioned an increased number of skin and cervical cancers in transplant patients on immuno-suppressant therapy. Likewise, more frequent lesions of the cervix have been reported in women undergoing prolonged chemotherapy and in patients suffering from auto-immune diseases or HIV-AIDS. Vitamin A deficiency also reportedly favours the appearance of lesions. Finally, the role of the male partner cannot be disregarded.

Infection targets and duration

• Low-risk HPV and genital condyloma acuminata: a disease of young women and men

The frequency of low-risk HPV infection peaks at between 15 and 25 years of age. It affects males and females alike.

Following exposure to the virus during sexual contact, the time it takes for any lesions to appear is from 2 to 8 months, with the average thought to be around 6 months. If low-risk virus strains are present without lesions, it takes an average of 4 to 12 months for them to disappear spontaneously.


• High-risk HPV and dysplasia, an infection which affects young people and afflicts adults

Exposure to the virus usually occurs following the onset of sexual activity but continues after this, too. The frequency peak is 30% on average at 25 years of age.

Clearance (or the spontaneous disappearance of HPV) more particularly concerns the high-risk HPV strains. It is 80% for under-25 year-olds and decreases with age. At 45 years, the probability of spontaneous disappearance of high-risk HPV is lower, due to immunity declining with increasing age. The average clearance time is from 8 to 12 months.

Persistence means the high-risk virus has not been eliminated naturally. In contrast to clearance, it increases with age. Immunity correlated with age plays a crucial role in viral persistence. Before dysplastic lesions appear, the virus remains in a latent state and during this time only a viral test can identify the presence of the infection, as the smear is normal. The average time it takes for a persistent high-risk HPV infection to cause dysplasia is estimated at 18 months.

Thus, in Europe, the average age for the onset of sexual activity is estimated at 17 years, the CIN3 frequency peak at 28 years and that of cervical cancer at 40 years. The main age range of women affected by high-risk HPV lesions is thus older than that for low-risk HPV, and the time at which symptoms appear is later, too.

Being over 35 years of age increases the risk of persistence

So-called cocktail HPV tests, i.e. those to detect all high-risk viruses, cannot measure persistence precisely. This is because, to be persistent, an HPV infection of the same viral type has to be present for a period generally of more than 12 to 18 months.

The genotyping techniques routinely available today have given us a better understanding of this process. Thus, it appears that infection with HPV 16 is one of the commonest. Its clearance is inferior and it is persistent more often than other types of high-risk HPV. In fact, an HPV 16 infection has a greater chance of persisting, and thus generating dysplasia, than all the other high-risk viral strains. This is doubtless due to a greater immune tolerance for this viral type. Thus, new, more precise and more reliable risk indicators are now available to help us understand and treat them.

The scale of HPV infection: cervical cancer, a rare complication of a common infection

Based on a worldwide population of 2.7 billion women, the frequency of cervical pre-cancers is estimated at 6 million in developed countries and 20 million in developing countries, meaning that 600,000 women are affected by cervical cancer in developed countries and 2 million in developing countries. This high frequency of papillomavirus infections and the lesions they generate raises an important public health issue.

The cancers attributed to HPV are first and foremost that of the cervix (100%), the anus (90%), then the vulva (40%) and finally the penis (40%).

If the HPV test is negative, there is practically no risk of having or developing pre-cancer of the cervix - subject, however, to this negative status being maintained for several months. If the test becomes positive, cell changes found in the smear can be considered to be probably abnormal - even if they are only minor changes - and, at this point, colposcopy and appropriate treatment can be planned.

In any event, even if the HPV test is negative, the screening smear must be carried out regularly. The link between sexual activity and the development of CIN has been demonstrated, and correlates directly to the risk of cervical HPV infection in young women. Today, it is also accepted that the role of the male partner influences this risk. In the risk of the development of CIN in women, the identification of spouses with more than one partner is an important aetiological factor. And if the young age of the onset of sexual activity as a cervical cancer risk factor is no more than a reflection of the early acquisition of HPV, the number of sexual partners can, for its part, translate into repeated exposure to the infection. Thus, exposure to a single partner is associated with the detection of HPV DNA by PCR in 2% of cases, while exposure to ten partners or more is clearly correlated to an approximately 69% increase in the detection rate. Let us not forget either, and I would stress this, that the disease is also observed in couples who have been stable for a number of years, and this testifies to the particular vulnerability of women to this widespread virus.

Despite the relatively high frequency of HPV infection in young women, CIN remains relatively rare at this age. For example, between 15 and 25 years of age, while the frequency of HPV infection reaches 30%, that of CIN is just 3% annually and cervical cancers are virtually non-existent. In women with normal smears, the prevalence of HPV infection clearly falls with age, from 30% between 15 and 25 years to 4% after 55 years. Conversely, the annual frequency of CIN, and more particularly cases of CIN3, increases with age. There is a highly peak between 25 and 29 years, with the reduction after 30 years probably being linked to early detection. At around the age of forty, the frequency of HPV infection stands at approximately 10%, and that of CIN3 at 1%. All of these elements suggest that, while the majority of HPV infections are transient, especially in young women, the impact of persistent HPV infection on the development of pre-cancers of the cervix remains significant.

But bear in mind that, of all the women who are screened, 3 to 5% have an abnormal smear every year. Of these abnormal smears, the vast majority, i.e. eight of every ten of them, show minor cell changes. Suitable treatment always resolves this problem. Approximately 1% of women who have smears have cell changes which can be considered high-risk. These lesions can be cured in almost all cases by colposcopy to locate the lesion and then treat it appropriately. Every year, around one woman in 10,000 is affected by cervical cancer in France. They are usually women who have not been screened on a regular basis. It is essential to remember the need for regular screening which will enable future pathological developments to be avoided in almost all cases.

Emotional and psychological impact of screening for HPV infection

The announcement of a smear or a positive HPV test triggers huge anxiety in many women. During the wait for the appointment with the specialist, which can last several months, this worry can feed on misconceptions which circulate on the internet. Even treatments, although actually fairly simple, are regarded as a trauma because they affect intimacy, increase the perception of the risk and are linked to fertility. Furthermore, the concept of sexually-transmitted infection can sometimes exacerbate uneasiness and suspicion between the couple.

How to discuss HPV infection with women, adolescents and parents

How to discuss HPV infection with women, adolescents and parents

Women have no knowledge of HPV infection, with few of them having even heard of it. The information provided in the various media is plentiful but often partial or incorrect. In view of the recent advent of preventive vaccines, practitioners and gynaecologists need to prepare their responses to a large number of questions about this infection and its consequences.

The main information needed by patients relates to: how the virus is transmitted, how the infection and the occurrence of lesions can be prevented; the treatments possible and how the lesions progress without treatment; the risk of cervical cancer. Simple and “customised” messages need to be provided urgently, based on age and risk profile.

Explain and de-dramatise

Talking about HPV is not simple and is a delicate task, especially as the patient needs to be informed about a cancer risk, while at the same time the situation needs to be de-dramatised; in particular, the physician needs to be able to respond to this type of questioning:

• To the question: “How can my smear be normal if I have HPV?”, an explanation needs to be provided as to the usefulness of the HPV test (i.e. detection of the virus) and its infallibility, in contrast to the smear, which is not always 100% reliable and sometimes gives a false negative.
• To the question: “If I have an HPV infection, does that mean I have cancer?”, the patient needs to be reassured by an explanation of the various stages of HPV infection, cancer being the final but rare, or even improbable, outcome if screening is carried out regularly.

In practice, a delicate balance needs to be established between a very precise discussion about the risk of pre-cancer (explaining the existence of the HPV infection and its potential impact) and a reassuring talk about the screening procedures which enable the risk of cervical cancer to be reduced to minimum or zero levels (in the vast majority of cases, nothing serious will happen).

The choice of words and phrases needs to be geared towards this dual objective. For example, if the words “pre-cancerous lesions” have been uttered, the patient will have heard the word “cancer”, which causes her anxiety levels to rise; the talk which follows therefore needs to provide reassurance. On the other hand, if the word “dysplasia” is used, a baffling word has been introduced that will not cause anxiety but does not explain the potentially serious nature of the condition; the talk thus needs to be steered to an explanation that the situation is not dramatic, as a simple treatment will provide a definitive cure.

A few tips for helping the physician to communicate with his patient

• Talk quietly and listen to the patient´s history.

• Use everyday language.

• Use images or stories to illustrate important points.

• Do not hesitate to repeat instructions, especially the important ones.

• Limit the quantity of information given at each meeting; if too much information is given at the same time, the patient cannot take it all in.

• Use the term “explain to me” or “show me” to confirm that the patient has understood, something which is not always done.

• Avoid saying “Do you understand?”, and instead get the patient to speak.

• Be respectful, understanding and kindly.

Unfortunately, there is often not enough time to adapt the information perfectly to patients´ needs. Consideration must also be given to populations of women who need particularly carefully-phrased remarks, as they are particularly badly informed; this means immigrant women, women living in rural areas, women of a low socio-economic level and illiterate women - cases which are not at all rare.

A few important points regarding the medical discussion

• HPV infection is the most frequent STD (sexually-transmitted disease).

• All women are at risk of developing HPV infection during their lifetime.

• HPV infection very frequently clears up spontaneously.

• The vast majority of women who are carriers of HPV will not develop cervical cancer.

• The purpose of the cervico-vaginal smear, possibly associated with an HPV test, is to screen for lesions caused by HPV. The right treatment is always successful in curing the condition.The majority of women who, in the context of a screening programme, have a negative HPV test are not at risk of having a pre-cancerous lesion or cancer of the cervix.

Talking about it to young girls

Here we are in the more general context of sex education. The discussion needs to be geared specifically for adolescent girls as, due to their young age, they have greater difficulty in differentiating between the purpose of a smear, a pelvic examination, a pregnancy test and screening for sexually-transmitted diseases (STDs). They are just discovering all these concepts and, in comparison with women who have a certain amount of experience in this regard, it can easily confuse them. They are more concerned by the concept of STD or unwanted pregnancy than by the risk of cervical cancer, which to them seems very remote. Thus, the prescription of a contraceptive pill is the opportune moment to address these issues.

Who can tell them about HPV infection?

Parents, as we all know, are not really the best people to provide general information about sex. On the other hand, the medical establishment (paediatrician, family GP, gynaecologist) or the school teacher can take on this task.

However, the people who are best placed to provide this kind of information are family counsellors, midwives and school nurses working in secondary schools and colleges, as the information needs to be comprehensive and not focused on just one risk. The difficulty with these educators is that they themselves are not always well informed and they would therefore first need to undergo training. In France, the system of mentors (students of the same age, or medical students working in schools to provide sex education), which has seen good results in other countries, has not been developed.

Sex education as it stands in France is about thirty years old. The last circular dates from 2001 (law no. 2001-588 of 4 July 2001 regarding the voluntary interruption of pregnancy and contraception, article 22) and stipulates that sex information and education is to be dispensed in schools, colleges and secondary schools by at least three sessions per year and in groups of students of a similar age.

To conclude

With the appearance on the market of vaccines to prevent HPV infection, consideration must be given to the current context: women - and to a lesser degree, the medical establishment - are very poorly prepared for it. They are still victim of a lot of received wisdoms and sometimes real misconceptions about this infection and the pathology associated with it. Gynaecologists therefore, all too often, are confronted by disproportionate anxiety on the part of their patients when a smear is abnormal or an HPV test is positive.

Thus, a major communication effort needs to be made not only for healthcare professionals but also for women, to remedy the situation. A number of problem areas need to be resolved; that of the infection, which is not like other sexually-transmitted diseases; that of its transmission; that of the interpretation of results and, above all, that of the anxiety caused by information about HPV.

By way of example, a European survey was carried out in which around one thousand women were asked about their perception of the disease and the infection. To quote just two figures: a mere 7% of women had heard of HPV infection and, of them, just 18% made the link between HPV and cervical cancer.

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