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Protecting women from cervical cancer

Every year an estimated 120,000 women in India develop cervical cancer and 80,000 of them die of it. The country accounts for about a quarter of the global burden of the disease. In much of the country, it is the most common form of cancer afflicting women, according to M. Radhakrishna Pillai, Director of the Rajiv Gandhi Centre for Biotechnology in Thiruvananthapuram.

The world over, infection by the human papillomavirus (HPV) is the primary cause for this form of cancer. This virus is sexually transmitted. There are about 80 HPV types, 30 of which are known to infect the genital lining, points out Dr. Pillai, who has been studying the virus for the last 15 years. But only some of these cause cancer. HPV types 16 and 18 cause about 70 per cent of cervical cancers that occur worldwide. There are also low-risk types that cause genital warts. However, even if a woman is infected with a high-risk HPV type, chances are that her immune system will clear it from the body. Only a small proportion of such women develop pre-cancerous lesions, and fewer still get cervical cancer.

In the developed countries, cervical cancer rates have been slashed: women there regularly undergo the ‘Pap smear’ test for early signs. In this test, a sample of cells is gently scraped from the cervix and examined under a microscope. If cellular abnormalities are found, further tests are done to check for pre-cancerous lesions. The pre-cancerous stages are easily treated with simple surgical procedures, says Dr. Pillai.

“In 2005, more than 60 million Pap smears were performed in the United States, and it is estimated that such screening programmes and intervention have reduced the incidence of cervical cancer by [about] 80 per cent cent in the United States, but at a cost of more than $6 billion a year,” noted Richard Roden and T.C. Wu of the Johns Hopkins University in a review paper published last year.

As there is no organised screening programme for cervical cancer in India, often women are likely to seek medical help only after the cancer has manifested itself, says Dr. Pillai. The problem may be diagnosed early in a few lucky women when they seek treatment for some other gynaecological problem.

Vaccination has traditionally represented the most cost-effective approach to combat infectious disease, say Dr. Roden and Dr. Wu. However, the U.S. Food and Drug Administration only last year licensed the first vaccine for HPV — Gardasil from Merck. A second vaccine, Cervarix, developed by GlaxoSmithKline, was recently approved in Australia. Both work by training the human immune system to recognise and act against the L1 protein that forms the outer coat of the virus. Gardasil guards against the high-risk HPV 16 and 18, as well as HPV 6 and 11 that produce warts. Cervarix provides protection against HPV 16 and 18.

The vaccines have been found to be efficacious against the HPV types they target, but do not offer protection if women have got infected by those HPV types prior to vaccination. “Vaccination before the initiation of sexual activity is optimal,” noted Dr. Roden and Dr. Wu. The FDA has approved Gardasil for use in women from nine to 26 years of age.

But the protection afforded by such vaccination has a high price tag. The three doses of the Merck vaccine needed to immunise a person cost an estimated $360 (about Rs.14,500) in the U.S.

“For countries with a gross domestic product of less than $1,000 per capita, the per dose cost may need to be as low as $1 or $2 to make vaccination both cost-effective and affordable,” said Jan M. Agosti of the Bill and Melinda Gates Foundation and Sue J. Goldie of the Harvard School of Public Health in a commentary published recently in the New England Journal of Medicine. Over the next year, the GAVI Alliance (formerly the Global Alliance for Vaccine and Immunisation ) will review its new-vaccine policies to determine whether HPV vaccine should be among the vaccines prioritised for support, they added.

Meanwhile, a team of U.S. scientists led by Robert Garcea of the University of Colorado School of Medicine and Richard Schlegel of the Georgetown University School of Medicine believes it has a candidate HPV vaccine that can be made available cheaply.

Merck has used genetically modified yeast to churn out the L1 proteins used. GlaxoSmithKline’s vaccine has been produced using insect cells infected with a modified insect virus. The Garcea-Schlegel team has genetically manipulated the widely-studied bacterium Escherichia coli so that it churns out the L1 protein fused with another protein, glutathione S-transferase (GST).

The advantage of using the bacterial system is that large quantities of the fusion protein can be produced and purified quite simply, says Dr. Garcea. “So we believe that the manufacturing costs will be extremely low,” he told this correspondent. As a result, the cost of the vaccine to the public could also be kept down. “We are aiming at a target of less than half a dollar a dose.” Besides, the GST protein makes the L1 protein more stable under adverse conditions and it may therefore become possible to avoid refrigeration. In addition, GST may help induce a stronger immune response to the vaccine, Dr. Garcea added.

He said the National Cancer Institute in the U.S. was funding Shanta Biotech, the Hyderabad-based biotechnology company, to produce the vaccine for clinical trials. Phase-I clinical trials in the U.S. could start next year. Once these were satisfactorily completed, subsequent clinical trials could be done in India.

Initially, the vaccine will be formulated to provide immunity against the high-risk HPV16. Once the formulation was tested and approved, “we can then add as many additional types as needed,” said Dr. Garcea.

While vaccination holds promise from a long-term perspective, “screening is the immediate answer,” given the current burden of the disease, according to R. Sankaranarayanan of the World Health Organisation’s International Agency for Research on Cancer at Lyon in France.

Pap smears had proved extremely effective in Western countries where such programmes were well-organised, there was considerable quality assurance, and women were screened at regular intervals, he said. However, massive investments were needed. Several Latin American countries that had implemented Pap smear programmes from the 1960s had seen no impact on the disease burden. So some of them were trying to reorganise the programme.

Recently, Dr. Sankaranarayanan and others wrote in The Lancet on trials among women in Dindigul district of Tamil Nadu. They had been screened using a technique involving visual examination. A group of women who underwent such scre ening had 35 per cent fewer deaths from cervical cancer compared to a group that had not been screened.

This reduction was achieved after a single round of visual screening, said Dr. Sankaranarayanan. Visual screening did not require a laboratory, the results were immediately available and it was cheaper.

Several developing countries were trying to implement visual screening programmes. These include Thailand, Bangladesh, Nepal, Zimbabwe, Tanzania, Guatemala, and Peru.

“Even if you cover a population adequately with HPV vaccine, because the vaccine is aimed primarily at young girls, its impact in terms of reducing pre-cancerous lesions and cervical cancer will be seen only after four or five decades,” said Dr. Sankaranarayanan. So screening will have to continue. Besides, there could be vaccine failures and cases occurring because of HPV types not covered by the vaccine.

Patti Gravitt of the Johns Hopkins Bloomberg School of Public Health found during her joint work to evaluate cervical screening in rural India that the biggest obstacle was the reluctance of women to undergo the pelvic examination required for either Pap smear or visual inspection-based screening. This was compounded by similarly poor compliance in the follow-up examination and treatment, she said in an e-mail.

Initial evaluation of ongoing research being carried out in Hyderabad into the barriers surrounding participation in cervical cancer screening and acceptability of HPV vaccine suggested “a much higher acceptability of HPV vaccine compared to screening, even if the vaccine is given to girls prior to marriage,” Ms. Gravitt noted.

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