New in South Africa:
Roche Diagnostics announces the formation of a
Woman’s Health Advisory Board
for the advancement of women's health by assessing information and issuing guidelines through its
that was formed as a partnership between SASOG and Roche Diagnostics with input from other interested parties.
Woman's Health Advisory Board
Report of a meeting held at Kloofzicht on 12-14 August 2005
This Board was convened by Roche Diagnostics, in partnership with the South African Society of Obstetricians and Gynaecologists (SASOG), as part of the Roche Women's Health Project. The Board consists of senior members of SASOG with a special interest in gynaecological oncology and who are considered to be opinion leaders in the field, a senior clinical pathologist and a senior microbiologist who is an expert in the field of sexually transmitted infections.
The Board is an independent body and is separate from the sponsoring company. No company employee is a members of the Board or has influenced the recommendations made by the Board. No members of the Board declared any conflict of interest or are employed by the company.
The objectives of the Board are:
To develop recommendations for the use of human papilloma virus (HPV) testing and to revise these on an ongoing basis
Cervical carcinoma is still the most common cancer of women on the African continent. Mortality remains high - worldwide at 50% - mainly because of late presentation, advanced stage of disease and absence of a functioning screening process. The aetiological link between human papilloma virus (HPV) infection and cervical cancer has been well established and a number of high-risk HPV genotypes have been identified. HPV infection is the most common sexually transmitted infection (STI) in the world today – up to 80% of sexually active females will harbour HPV at some point in their lives. The majority of women will experience natural elimination of HPV infection because of an intact immune system. Persistent infection with a high risk type HPV puts women at high risk to develop precursors of cervical cancer or carcinoma itself. As part of a public health response to this serious problem several HPV vaccines are under development. Use of vaccines still poses unanswered questions in many respects.
The precursors of cervical cancer can be detected and treated. The most important aspect of detection is screening of asymptomatic women. The Pap smear is generally used for this purpose. If this is used with wide coverage in a population Pap smear screening has been shown to lead to a drastic reduction in the occurrence of cervical cancer in that population.
As more information becomes available about HPV and as tests for accurate detection of HPV have been developed much of current discussion on cervical cancer and its precursors should centre on HPV, the role of HPV testing and the clinical use of these tests in South Africa .
Screening for cervical cancer
Screening programmes aim to reduce mortality and morbidity from cervical cancer and to decrease the number of patients suffering from cervical cancer. Through screening the existence of precursor lesions of the cervix can be detected and managed. Basic screening programmes can lead to downstaging of cervical cancer which offers benefit for patients in its own right.
The National Policy on cervical screening allows for 3 smears in a woman's lifetime taken at 10 year intervals from 30 years of age. This policy has been implemented in some areas but not throughout the country. The National Health Laboratory Service where cytology laboratories in the public sector are to be found has not fully rolled out a programme to become a part of the process. Several initiatives for screening are starting or are in the planning stage: this includes initiatives from the National Department of Health, its Directorate of Maternal and Child Health and some provincial Health Departments. Over the years several proposals for screening made by academics and professional societies were rejected by policy making authorities, frequently on the basis of perceived high cost. The result is that currently there is no population wide screening programme in South Africa . In several areas partial screening does take place. In the private sector opportunistic screening is commonly practiced.
In populations where coverage is wide enough to reach more than 70% of women the maximum impact of decreasing the incidence of cervical cancer and cervical cancer deaths becomes apparent and plateaus out at 84% coverage. It is expected that the occurrence of cervical cancer can be reduced by 70% or more under such circumstances. In such programmes the frequent recall of women led to huge cost increases that in turn resulted in curtailment of the programmes in many areas. Current recommendations include that the first Pap smear should be taken at age 21 years or within 3 years of onset of sexual activity. Thereafter smears should be taken annually until age 30 after which smears should be taken every three years, concluding the screening at age 65-70 years for those women who have had persistent normal smears.
In developing countries the objectives are very different. The WHO advocates one smear (at age 30-35 years) in a woman's lifetime as the least to be performed. Never having had a Pap smear remains one of the highest risk factors for the development of cervical cancer.
The Pap smear has a lower than expected sensitivity of only 54%. This is improved when liquid based cytology is used. Cost of a national population based screening programme is a serious obstacle. Lack of capacity, lack of treating facilities and lack of knowledge in the patient population all prove to be huge obstacles. The HIV pandemic is a massive obstacle in several respects.
Ideals for cervical screening in South Africa include the achievement of wide enough coverage of the female population to impact on the health of the women of South Africa, the empowerment of women to expect and indeed demand proper screening programmes to be in place, and improved popular education and awareness. Better knowledge may lead to increased acceptance of screening requirements by women, including acceptance of the need for follow-up visits. The highest ideal is improved sexual health for the population. Other ways of screening should be developed and assessed to overcome the problems and impasse of the current programmes. Capacity for diagnosis and treatment must be increased.
HPV are mucosotropic DNA viruses that cause most of the malignancies of the anogenital tract. More than 100 HPV genotypes can be defined of which more than 40 infect the anogenital tract.
HPV infections are the most common sexually transmitted infections today. Based on research findings of the last two decades the firm conclusion has been reached that infection with a high risk HPV genotype is regarded as the primary cause of cervical cancer. Cervical carcinogenesis involves several cofactors – not all well understood or of equal importance – including cigarette smoking, poor nutrition, folate deficiency, HIV infection, genetic predisposition and the possibility of other genital infections such as with herpes simplex virus.
Certain high risk HPV types have been identified relating strongly to cervical carcinogenesis. Types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73 and 82 have been linked to cervical cancer. The virulence of these types differ. Some genotypes have been identified as of intermediate risk namely 23, 53 and 66. The low risk HPV types cause genital warts but not cancer.
HPV is easily transmitted but requires entry into the basal layer of the cervical epthelium at sites of micro- or macro-trauma. Most HPV infections are transient and persistent infection with a high-risk type of HPV poses a carcinogenic risk. When the cervix is infected with HPV mild cytological abnormalities are frequently present. Persistence of high risk HPV over time contributes to occurrence of random mutations leading to cervical cancer. Once HPV is integrated into the host genome severe cytological abnormalities are found and the histological diagnosis of cervical intraepithelial neoplasia (CIN) and eventually cervical carcinoma can be expected.
The different HPV types have been shown to have different viral persistence, different potential for viral integration and also different carcinogenic potential. The proportions of viral types in cervical cancer specimens therefore do not reflect the incidence of these viruses in the population, but rather their nature. Its is known that HPV type 16 alone causes about two-thirds of all cervical cancers worldwide and it is therefore the main pathogen.
Testing for high risk HPV
Currently available tests will detect the most common high-risk HPV viruses present in the sample. The different tests have subtle differences regarding the viral types included in the test battery. Commercially available tests in South Africa reflect active infection of the cells with HPV but do not test for viral integration into the genome, which is the carcinogenic event. The presence of HPV is therefore accurately established but not the state of the disease process.
Test results can be reported as either positive or negative for the presence of high risk HPV. Alternatively the list of high- and intermediate risk HPV types found in the sample can be reported. The clinical significance of presence of multiple HPV types or changes in the HPV types over time is not currently known. The list of viruses-type of result does not have any clinical importance or superiority above a simple positive or negative answer but may have useful research implications.
HPV-DNA can be isolated from various samples. Physician sampling has been performed over years. Recently patient self-sampling was developed.
Physician sampling with cervical swab or brush or spatula has been found adequate. It is not imperative to obtain take the sample from the transformation zone and a sample taken from the posterior vaginal fornix or vaginal walls is adequate. Sampling in different areas of the vagina and cervix may render different results and different HPV–types can be found. The prognostic importance and clinical impact of these differences are not currently known.
Self-collection obviates the need for speculums, examination rooms and trained personnel and will have an important impact on the cost of screening. It has been found to be more acceptable to women than traditional Pap smear testing and the expectation is that this method will improve uptake. This has to be seen as a significant potential advantage. Self-collected samples for cervical cytology markedly decrease the sensitivity of the test unless the device is left inside the vagina for 10 minutes or longer. Some tampons need to be inserted for at least an hour. Vaginal swabs tipped with Dacron can be used with ease and collection with two consecutive brushes render better results than using a single one. Self-collected samples will render good results when DNA based testing is used.
Physician sampling and patient self-sampling have been extensively tested and both have been found to produce satisfactory and comparable results. The reason for this is that PCR (polymerase chain reaction) amplification of DNA makes the test method highly sensitive.
Samples can be transported dry or in an essential buffer solution, depending on the sampling method and device used. When liquid based cytology is used, the same liquid used for cytology can be used for HPV testing.
The cost elements of HPV testing include the sampling device and transport method, the laboratory and personnel costs and the cost of the test kit used for DNA extraction, PCR and costs to read and report the result. The cost elements of screening also include the cost of the facilities and personnel to do initial sample collection, management of women with abnormal results and all communication between the provider and the patient. It is complicated to calculate the cost of different screening programmes and to compare these, as large differences in collection methods and call back rates exist.
Various authors have calculated cost of HPV based screening and compared it with existing cytology testing. HPV testing as a primary screening method may be cost effective when compared with existing protocols but these analyses are highly situation and protocol specific.
An attempt will be made by the Board to do cost analysis on the three recommended screening protocols (see annexures) and the results will be communicated at a later stage.
Clinical uses of HPV testing:1 Primary screening of a low risk population
High risk HPV testing offers several potential advantages over conventional cervical cytology in the setting of primary screening but also has many limitations.
HPV testing is significantly more sensitive than cytology to predict cervical cancer and its precursors. The sensitivity of the test approaches 100% due to the ability of PCR to detect HPV DNA even when present in minute quantities. This high sensitivity and the long interval between infection and invasive cancer mean that HPV negative woman can safely have a considerably longer screening interval than when using a cytology-based screening programme. The recommended screening interval will differ between countries and will depend to a large extent on available resources. In many countries even a once-in-a-lifetime screening with the much less sensitive cytology test is still to be reached! Most cytology based screening programmes compensate for the low sensitivity of a single test by repeating cytology every three to five years. This strategy leads to a high sensitivity of the screening programme but is expensive to implement.
It is apparent that HPV testing seems to be a much better test to use in any programme with once-in-a-lifetime testing or with long screening intervals (> 5 years). Longer screening intervals are more cost-effective overall.
Certain subgroups of the population are NOT suited to HPV screening due to a very high prevalence of HPV. This includes women under the age of 30-35 years where HPV has been reported to be present in up to 80% of women and where its presence is mostly transient. In immune compromised women the incidence of HPV is also high but the high negative predictive value can be useful as a triage method.
A large proportion of women already know about Pap testing, while HPV testing is new. The diagnosis of HPV infection may have a negative psychological impact on the woman. There is also a potential for confusion with HIV in the mind of the patient.
HPV testing is a very good indicator of prognosis in several clinical situations and can therefore successfully be used to triage patients. The absence of high risk HPV accurately predicts a very low risk for cervical carcinoma and absence of this disease for many years to come. This finding can be used to discharge patients from strict follow-up in various clinical circumstances. In a patient after the age of 30 years a finding of negative HPV plus negative cytology is regarded as highly predictive of no CIN lesions or cervical cancer and this patient needs very few screening episodes in her life (the “Super test”).
On the other hand HPV positivity can predict future disease with some accuracy even in patients who are cytologically negative. Persistent HPV strongly correlates with future disease and is an indication for strict follow up or even for treatment.
A Ambiguous or low risk abnormal cervical cytology
If a patient had a low risk abnormal cytology result, HPV testing can identify those who test HPV negative who can be followed up with a relatively long interval of up to 10 years, and those who test HPV positive who can be offered treatment or close follow-up (see Flow diagram C).B Follow-up after treatment for pre-invasive and invasive cervical disease
Women who test positive for HPV during follow-up after LLETZ or similar treatment for CIN lesions have a much increased risk for recurrent disease. Specific follow-up protocols have not been evaluated and most reports refer to the first follow-up visit. The most likely implication is a recommendation for a tight follow-up schedule for HPV positive patients.
Women found to be HPV negative can be screened with normal screening intervals, while HPV positive woman must have increased surveillance or treatment.
The next steps
Roche Diagnostics may sponsor a visit of a key international opinion leader to South Africa .
The final report will be widely distributed including communications with family physicians and medical officers.
Signed on behalf of the Board
Prof BG Lindeque
• Dr Hennie Botha MMed (O&G) FCOG(SD).Head: Unit for Gynaecological Oncology, Tygerberg Hospital and Stellenbosch University .
• Prof Bruno Cooreman MDSenior Consultant, Dept Obstetrics and Gynaecology, University of the Free State , Bloemfontein , SA
• Prof Greta Dreyer MBChB, MMed(O&G) MCOG(SA)
Principal specialist, Pretoria Academic Hospital and Adjunct Professor, Dept Obstetrics and Gyanecology, University of PretoriaHead of Gynaecologic Oncology Unit
• Prof Franco Guidozzi FCOG(SA) MRCOGChief Specialist and Academic Head: Dept Obstetrics and Gynaecology, University of the Witwatersrand
• Prof Anwar Hoosen MSc, MBChB, MMed (Microbiological Pathology) FCPath(SA)Head; Department of Microbiological Pathology, Faculty of Medicine, MEDUNSA Campus, University of Limpopo
• Prof Tony Koller MBBCh, DipMid COG(SA), FRCOG, FOG(SA)Adjunct Professor: Department of Obstetrics and Gynaecology, Johannesburg Hospital , School of Clinical Medicine, University of the Witwatersrand, Johannesburg . Consultant Gynaecologist in private practice.
• Prof Gerhard Lindeque MBChB, MMed(O&G), FCOG(SA), MDProfessor and Head: Dept Obstetrics and Gynaecology, University of Pretoria . President of SASOG
• Dr Louis Marcus MBChB MMed (ClinPath) DTM&HClinical Pathologist.
• Dr Manivasan Moodley MBChB MMed(O&G) FCOG(SA)Principal Specialist/senior lecturer and Head: Gynaecologic Oncology, Nelson R Mandela School of Medicine and Inkosi Albert Luthuli Central Hospital , University of KwaZulu-Natal
• Dr Arrie Mouton MBChB M Fam Med MMed (O&G) FCOG(SA)Senior Specialist, Dept Obstetrics and Gynaecology, University of pretoria , PO Box 667 , Pretoria 0001
• Dr Trudy Smith MBBCh, FCOG(SA)Principal Specialist, Johannesburg Hospital , Senior Lecturer, Dept Obstetrics and Gyanecology and Gyanecologic Oncology Unit, University of the Witwatersrand
• Dr Robbie Soeters MD PhDHead: Gynaecologic Oncology Unit: Groote Schuur Hospital , University of Cape Town
Frequently asked questionsWhat is Cervical cancer?
Cervical cancer affects the mouth or the part of the womb that opens to the vagina. It is still common in Africa and many other countries and it occurs worldwide. Less women than before get cervical caner if a Pap smear or other screening strategy is followed in a country. Early detection of cervical cancer contributes much to an improved outcome.What is a CIN lesion?
A CIN lesion means “cervical intraepithelial neoplasia”. This means that the skin of the cervix has become abnormal and that if this condition is left untreated over time this abnormality will become worse and even develop into cervical cancer. In this sense CIN is a precursor or early warning lesion. It can be detected on Pap smears and can be treated effectively. This will prevent the development of cervical cancer in most instances.What is HPV infection?
HPV stands for “human papillomavirus”. HPV infection is common in sexually active persons. It is mostly harmless and tends to disappear on its own as the body eliminates the virus. There are many types of HPV but only a few types can lead to cervical cancer. These are called “high-risk types” and spread through sexual contact. If a high risk HPV type does not disappear on its own it can lead to the formation of abnormal cells in the skin of the cervix leading to a CIN lesion or later to the development of cervical cancer. In such cases treatment must be offered. Low-risk HPV types cause genital warts and do not cause cancer. How common is HPV?
HPV can be found in the genitalia of the large majority of sexually active persons at some stage in their lives. As the infection is mostly temporary most women will not have any HPV by the age of 30 to 35 years.Who is at risk and can get HPV and CIN?
All persons, male and female, who have been sexually active can get HPV infection. About three out of every four persons are estimated to have HPV infection at some stage in their lives, usually when quite young (late teens and twenties). Women who start with sexual activity at a young age, who have several sex partners or whose partners have or had several partners are at increased risk for having HPV infection.
It is now known that almost all cervical cancers are caused by HPV. Women who are at risk for HPV infection are therefore also at risk for cervical cancer if the HPV infection is of a high-risk type. The cervical cancer risk is increased by other factors such as smoking and HIV infection. As Pap smear and other screening tests for CIN and cervical cancer are very important in the early detection of abnormality women who have had no such screening tests are at the highest risk of all.How is HPV diagnosed?
HPV infection rarely causes symptoms. Infection with a high-risk HPV type will lead to abnormalities in the cells covering the cervix that can be detected on special HPV tests and on Pap smear testing. Only a small number of women with HPV will develop cell changes.Can HPV infection be treated?
There is no treatment against the HPV itself. If the cervical cells have undergone changes and have become abnormal those areas on the cervix can be treated.Who should be tested for HPV infection?
The HPV tests are used to detect high-risk types of HPV. It can be used with most success in women over the age of 30 in many cases together with Pap smears. In women younger than 30 years HPV is quite commonly present and in the large majority it will be eliminated. To do HPV testing on young women does not contribute much to her gynaecologic management.Where did I get this HPV infection?
HPV is spread through sexual activity. The HPV can be dormant or resting for a short to very long period before causing cellular abnormalities. It is not possible to link HPV infection to a specific episode or time.Can HPV infection go away on its own?
In the majority of women HPV infection is transient and will be eliminated by the immune system of the body. HPV infection may persist especially after age 30 years or older.Can I do other things to help HPV disappear?
Yes: stop smoking as this can increase the risk for development of cellular abnormalities on the cervix. Maintain good sexual health and take care of your relationships.What is the difference or relationship between HPV and HIV?
HIV is also a virus: the human immune deficiency virus. This is currently a massive health care problem especially in developing countries but also worldwide. It is linked to the development of AIDS. It is very different from HPV. Persons who get HPV infected and who are also HIV infected may have a more serious outcome of the HPV infection. Like HPV, HIV is transmitted sexually.Does my partner need to be tested for HPV?
If you have a positive HPV test showing that you have infection with HPV it is absolutely likely that your partner will also have HPV infection. As most HPV infections are transient and tend to disappear it will not always be the case that both partners test positive. As there is no treatment against HPV testing the partner does not contribute to management. As condom use offers incomplete protection partner HPV testing will not influence this practice either.Do we have to use condoms now, and for how long?
As HPV infection is common condom use will not be total prevention. If you had treatment it is not certain (but possible) that condom use may decrease the risk of recurrent infection.After treatment can I be re-infected by my partner?
If a couple only has sexual relations with each other HPV will not be passed back and forth. Further contact with the same virus will not make it more difficult for either the HPV infection to go away or for cellular changes to be treated. Once a person has formed immune reaction to a specific HPV type a next exposure may be eliminated. There are however many HPV types and a person can get re-infected with another HPV type.Can I still get pregnant if I am infected with HPV?
HPV does not cause infertility. There are many reasons for infertility and this may include other sexually transmitted infections.How will it affect my baby and my pregnancy if I am infected with HPV?
HPV infection does not influence the course of the pregnancy. If a person has genital warts (low-risk HPV infection) these may increase in size during pregnancy. If a baby is born from a mother with extensive genital warts there is a possibility of infection of the newborn.Does it affect other organs and can it spread?
HPV infection can also have effects on the vulva and the vagina and it is possible that HOPV infection can spread from the cervix to these organs. It can be detected during clinical examination.