The National Cancer Institute (Inca in the Portuguese acronym) estimates that 19,260 Brazilians will be affected in 2006 by cancer of the uterus colon, the most common among women after breast cancer. Throughout the world, the illness, most frequent between 35 and 45 years of age, hits around 470,000 women per year – and kills half of them. “In Brazil it brings about more deaths in the female population than Aids” alerts the biologist Luisa Lina Villa, from the Ludwig Cancer Research Institute. The best form of combating the problem is to encourage preventative gynecological examt, since this tumor is brought about by some types of human papillomavirus, the HPV. Almost always transmitted via sex, these viruses install themselves in the vagina and in the tissue at the entrance to the uterus, where they unchain lesions. Even for this year the possibility of the control of cervical uterine cancer should be widened by the arrival of a preventative vaccine on the international market. This is a significant advance that reinforces the strategies in combating the virus focused in women.
But the vaccines will not be sufficient. For a more efficient control of the dissemination of HPV one needs to take into consideration a player that only recently became perceived with due attention: man, at the same time a victim and responsible for the transmission of HPV. “If we don’t include the partners in this process, it’s possible that the same woman, after having eliminated the virus, can again be infected” points out Luisa. She participated in a study coordinated by the University of Caxias do Sul, published in February in the Brazilian Journal of Medical and Biological Research, which analyzed the relationship between HPV and the male population.
The results show that, of the 99 men evaluated, all partners of women with cervical uterine rus cancer, 54 showed they had the genetic virus material – of these, only 28% had developed evident lesions, such as warts on the penis. As yet it is not possible to know the original path of contamination, if it be man to woman or the opposite, but the work indicates a dangerous situation, since men do not have the habit of carrying out tests to detect the infection. In general the doctor is only sought out when warts appear and these are found in 3% to 5% of men.
The study confirmed as well that the male sex, although on a lower scale, can suffer the consequences of infection by the virus – at times very serious. At the upper limit it is possible that the lesions transform themselves into penis cancer. It is true that this type of tumor reaches only two out of every 100,000 men annually. “But it’s a ghost that needs to be known in more detail” recognizes Luisa, responsible in Brazil for the coordination of the studies that resulted in the first preventative vaccine against HPV to arrive on the market.
Knows as quadrivalent vaccine, this vaccine was approved at the beginning of June by the Food and Drug Administration (FDA), the American agency that controls the release on of medicines. It protects against four types of HPV – the 16 and the 18, responsible for at least 70% of the cervical cancer cases, as well as the 6 and 11, related to 90% of genital warts in men and women. “More than 100 types of HPV are known, which are capable of bringing about simple problems, such as genital warts, and others much more serious such as invasive cancer” explains Luisa. By the end of this year, a second preventative vaccine should arrive on the European market – named bivalent, which takes this name as it acts exclusively against types 16 and 18 of the virus.
Guaranteed for women, the benefits of the two vaccines for the male population still need to be confirmed. Whilst the results do not emerge, the way out is to look for strategies that combat HPV that include this group, a task that is not easy. First, it will be necessary to overcome the cultural taboo: to admit that the male sexual organ, the symbol of virility, is not invulnerable. “Men keep on repeating ‘it’s not my problem, I’ve nothing, why do exams?'” says Luisa. The next task: to find alternatives to the peniscopy exam, which uses a magnifying glass to detect signs left by the virus in whoever has been infected. “Depending on the region of the penis from where the material for analysis is removed, the result can give negative. But the HPV could well be in another part of the genital organ” explains Cecília Maria Roteli-Martins, a doctor at the Nove de Julho and Leonor Mendes de Barros hospitals, both in the city of São Paulo city, and one of the participants in the studies carried out in Brazil concerning the bivalent vaccine. Another problem is that the peniscopy exam could indicate contamination by HPV when in fact this does not occur – a result known as false-positive, which can lead to the carrying out of unnecessary exams such as a biopsy, in which a small sample of penis tissue is removed.
In the opinion of Cecília, the fundamental idea is to educate men to use condoms, as well as widening studies into the male population. “This is a tendency that is beginning to be shown” comments Cecília. Attentive to this need, Luisa has started, in partnership with teams from the United States and Mexico, a study that will involve 3,000 men aged between 18 and 45 years in order to evaluate the impacts of HPV upon the male population. The first results should be known by the end of this year.
If in the case of men the trajectory is only beginning, the road in relation to the female segment has arrived at a special moment. The clinical tests show that the quadrivalent vaccine protects both against the development of warts and uterus colon cancer, without any important side effects. The protection can extend for a period of five years. The studies involved close to 18,000 women, aged between 16 and 25 years, in some 33 countries – among them, Brazil, the United States, Germany and Canada. The results were divulged in April in Paris during the European Research Organization on Genital Infection and Neoplasia (Eurogin) Congress. In Brazil the expectation is that the product, produced by the North American laboratory MerckSharp & Dhome, should be liberated by December by the National Health Surveillance Agency (ANVISA).
Anti-HPV belt
Also called virus-like particles (VLP), the vaccine stimulates and fools the human organism. The strategy is simple: it inserts itself in a vector, the L1 gene, responsible for the production of the main protein of the HPV capsule. This vector, in general a virus, infects the yeast of beer, Saccharomyces cerevisae, and makes use of the multiplication systems of the genetic material. Thanks to genetic engineering it is possible to extract from the yeast copies of the L1 gene without the genetic material of the viral vector, or that is to say, an empty and inoffensive virus. This is the vaccine, applied to women in three doses over a six month period. “As it imitates the HPV, the body understands that its time to combat the invader” explains Luisa. Women who receive the vaccine produce as much as 50 times more antibodies than those not vaccinated. When the HPV penetrates the body, in general close to the entrance to uterus, the concentration of antibodies increases in this region, forming a belt that avoids the installation of the virus and infection.
The bivalent vaccine follows the same logic in its action. However, its production makes use of a different vector: the baculovirus, a virus that infects insects. In this case, the studies, financed by the GlaxoSmithKline laboratory, with its head office in Belgium, involved around 18,000 women in 25 countries. The results indicate that protection, the same as that with the quadrivalent vaccine, is 100% and without any side effects – and even better, the protection can last up to ten years. The request for the commercialization of the bivalent vaccine was made in March to the European Agency for the Evaluation of Medicinal Products (Emea), an organ similar to the FDA.
Faced with the scenario where two vaccines present themselves with a prevention guarantee, Cecília is working with the idea one complementing the other. “There’ll be two efficient alternatives and we’ll have the prerogative of making options, following the specificity of each population and the types of virus most commonly found” she evaluates.
The arrival of these vaccines on the market has intensified the debate about which age group must be the campaign target for vaccination. In the United States the vaccine was approved for women from 9 to 26 years. For the Brazilian researchers, the ideal is that it reaches the female population who have not yet initiated their sexual life – and not to allow them to be contaminated by HPV. “I believe that this procedure must involve pre-adolescents and adolescents, in the age group of 10 to 15 years” postulates Luisa. The 2000 Census by the Brazilian Institute of Geography and Statistics (IBGE) estimated that there are approximately 9 million Brazilian women in this age group.
But there is an obstacle: the cost of the vaccine could make it inaccessible to the majority of Brazilian women – to have an idea, the three doses necessary for the quadrivalent vaccine should cost around US$ 360 in the United States. “The vaccine is an alternative of promissory prevention, which can be a failure because of its high cost” admits Luisa. “My challenge is to stimulate negotiations between the government and business with the objective of making viable the incorporation of vaccines into public policies for combating the HPV” says the biologist who for 25 years has been investigating ways of detecting and combating the virus. In the opinion of Luisa, the government will have to make a political decision and transform the combating of cervical uterine cancer into a priority, the same as that which happened in 1990 with Aids treatment. “We’re talking about investments in Public Health” she underlines.
Even at that it is questioned as to whether this investment is not elevated in relation to the population potentially benefiting, since the vaccine will only have effects on women as yet not infected with HPV. “It’s important, but it will have a specific action and will not cover all of the population” says Marcos André Félix da Silva, from Inca’s Oncology Attention Division. Luisa insists: “We can continue spending with treatment or we can channel these resources towards prevention.” In the end, even for the women who have already begun their sexual life, the quadrivalent vaccine can bring benefits, according to Dr. Luisa. If the woman has only one of the types of virus – the 6, for example – and receives the vaccine, she will become protected against the other three (11, 16 and 18). Even if she had been infected by the four types, there are indications that there will be 30% less chance of developing precursory lesions of the cancer.
“This is a universal vaccine” defines the researcher from the Ludwig Institute. And it will possibly also work for men. The expectation is that by 2007 ongoing tests will confirm the efficiency of the vaccine to also protect men from the HPV infection. But the checkmate will come – if it comes – with a curative vaccine, capable of destroying already developed tumors. Luisa is working on the development of this vaccine in partnership with researchers from the University of Colorado, United States, with financing from the Bill and Melinda Gates Foundation. The idea is to deactivate the virus’s E6 and E7 proteins, the ones with the highest carcinogenic potential, and to bring about an intense reaction of the defense system that eliminates the cancerous cells. Still in its initial phase, the experiments on laboratory animals have been demonstrating animating results.
Prevention and treatment
Whilst awaiting the release of preventative vaccines in the country, the specialists have reinforced the need to intensify the combat against the HPV by way of preventative gynecology accompaniment and of the realization of exams such as the pap smear exam, which indicates the presence of lesions and can be done through the Public Health System (SUS). For example, depending upon the diagnosis of the suspicion of cancer, the woman is sent for a second test called a colposcopy in order to confirm the location and the extent of the lesion before defining treatment – in the most serious cases there will be surgery for the removal of the uterus. During 2005, the Ministry of Health carried out 11.5 million papanicolau exams and 1 million colposcopys. “These are efficient procedures for the precocious detection of warts and tumors” says Dr. Félix da Silva. “But the coverage is very low. It’s calculated that only 15% of Brazilian women carry out regular prevention tests” adds Luisa.
The aversion of Brazilian women to that which should be routine is partly explained by misinformation and by the discomfort caused by an examination in the genital region. As well there are cases of patients who seek out public health clinics, carry out the material collection for analysis and never return to look for the results. “Women who live in cities are contemplated, which does not happen in the countryside” completed Dr. Cecília. A study by the Hospital das Clínicas (HC) of Sao Paulo given out in May contests the efficiency of this standard procedure – a papanicolau exam, followed by colposcopy – in determined situations. In the first instance, 90% of 60 young pregnant women between 12 and 18 years did not have the HPV. But on carrying out a more sensitive exam, known as hybrid capture, it was revealed that 51% of them had the virus’s DNA. “Because of the cost” observes Waldemir Rezende, from the HC’s Obstetrics Division of the Central Institute and a research coordinator, “the capture can’t be incorporated into the public health network as routine.” In the opinion of Dr. Luisa, this test must not be done in an indiscriminate manner, as it detects lots of infections not associated to uterus cancer.
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