Juliet Bowater

With cancer costs in the USA spiralling into many tens of thousands of dollars

, and costs of some new biological treatments approaching £100,000 

, you could be forgiven for overlooking cancer interventions in developing countries as too expensive to be cost-effective.

Not so, according to the 2015 Disease Control Priorities 3rd Edition (DCP3)

cost-effective cancer intervention and treatment strategies

, offering an “Essentials Cancer Intervention Package” designed to reduce deaths from cancer, tailored to the wealth of a country and the infrastructure available. The 2011 World Health Organisation (WHO) “Best Buys” document

 also details highly cost-effective strategies for cancer intervention which could save millions of lives in the coming century, and which require relatively little infrastructure.

Cancer incidence worldwide - DCP-3 cancer report

Tobacco-related deaths are increasing rapidly, especially in low and middle income countries (LMICs)

, and tobacco use threatens to kill far more in the coming decades than it has in the past. By the middle of this century, it has been estimated that tobacco-related deaths will reach 10 million per year

With up to 2/3 of smokers dying of smoking-related diseases

 and losing, on average, 10 years of life (DCP3)

, it’s hardly surprising that both the WHO and DCP3 recommend tobacco intervention as one of their top global health priorities. In 2013, the World Health Assembly introduced a target for tobacco control 

, calling for a 1/3 reduction in use by 2025, with the aim of saving 200 million lives.

Tax boosts to increase cigarette price have been shown to reduce smoking, especially amongst young people 

. A report by the World Bank estimated that for every 10% increase in cigarette cost, tobacco consumption would drop by 4% in high income countries (HICs) and 8% in low income countries (LICs). Young people are also more likely to quit and less likely to start when prices are high

The WHO therefore recommends that excise taxes should account for 70% of cigarette cost

. A report by the Asian Development Bank stated that increasing the price of cigarettes by 50% through taxation would avert 27 million tobacco-related deaths in China, India, Thailand, the Philippines and Vietnam alone

. Price increases hit the poorest smokers in a population hardest 

but the taxes are not considered to be regressive

 since those with low income are the most likely to quit and gain the intended health benefits (for more information on this see our blog post - 

“Is Tobacco Control a “Best Buy” for the Developing World

Alongside price increases, education is also vital. The WHO Global Adult Tobacco Survey for China showed that only 23% of Chinese adults knew that smoking caused lung cancer, heart attacks and strokes

. This lack of awareness affects the poorest in a population the most, with those who are illiterate unable to read warning labels.

Pictorial warnings have been used to try and re-balance this inequality in some countries

, and there is evidence that pictorial warnings improve awareness of dangers of smoking and reduce the number of young people starting 

. Packaging controls are also important in reducing the impression that some cigarette brands are less harmful than others 

Total advertising bans have been effective in reducing cigarette consumption

, especially in low/middle income countries (LMICs)

, and bans on smoking in the workplace have also been shown to reduce consumption 

Large investments from The Bill and Melinda Gates Foundation and Bloomberg Philanthropies have gone towards increasing awareness of the dangers of tobacco, funding research and collecting data, and pushing for changes in policy to reduce tobacco use

Liver cancer has one of the highest mortality rates of any primary cancer. In 2012, it caused 746,000 deaths out of 782,000 cases 

. Highly cost-effective interventions are available to reduce the number of people who get the disease, and these interventions are recommended by both WHO and DCP3.

Hepatitis B vaccination is the first line of defence. Hep B is a cancer-causing virus responsible for around 60% of hepatocellular carcinoma (the most common type of liver cancer) in LICs 

. The virus attacks the liver, sometimes setting up an infection which can last for years. 15-45% of those with long-term infection will develop serious complications such as cirrhosis and liver cancer during their lifetime 

The majority of countries now aim to vaccinate children at birth, but coverage at birth is still low in some areas 

. Initial vaccination within 24 hours is very important in preventing mother-child transmission, which often results in dangerous long-term infection

. Increasing vaccine coverage should decrease Hep B infection rates and hence liver cancer incidence

 has more information on the cost-effectiveness of vaccination. As with 

, Giving What We Can did not find any promising vaccination funding opportunities.

Targeting other region-specific causes of liver cancer may also be cost-effective. High rates of liver fluke infection occur in some areas of eastern Asia, especially within the Mekong River Basin in Southeast Asia, where around 40 million people are infected

. The worms can infect a host for many years, causing damage to the liver’s bile ducts which can eventually lead to cancer

. Treatment with Praziquantel can clear the infection, though people in the area are often quickly reinfected by eating raw fish dishes 40.

Liver flukes are not the only parasite to play a role in cancer. Infection with Schistosoma haematobium has long been associated with bladder cancer 

, and is recognised as a cause of cancer by the IARC 

. Studies in the 1970s and 80s noted that bladder cancer was more common in areas in which Schistosoma haematobium infection was common

 and biopsies of tumours showed high incidence of schistosome infection 

. This neglected tropical disease is easily and cheaply treatable, and two of Giving What We Can’s recommended charities - the 

 - can provide treatment for around $2 per person per year.

Poor food storage can also lead to higher rates of liver cancer. Aspergillus flavus and Aspergillus fumigatus can infect staple foods during cultivation, including peanuts, rice and corn

. In areas where these foods are then stored in warm, high humidity environments, the fungus is able to grow, producing the highly potent aflatoxin. This toxin causes DNA mutations and is associated with both liver and lung cancer.

In people with chronic Hep B infection, exposure to aflatoxin increases the chance of liver cancer by 30-fold. Improved grain storage and cultivation methods can reduce the amount of the toxin that people consume, and with 4.5 billion people currently exposed to aflatoxin, the potential for reducing suffering is enormous.

The final WHO “Best Buys” are designed to reduce deaths from cervical cancer. Screening and treatment for early cervical lesions have been shown to be cost-effective. Opportunistic screening with an acetic acid test is low-cost and cancerous/precancerous lesions can be removed on the same day 

Since high-risk strains of Human Papilloma Virus (HPV) are responsible for up to 98% of cervical cancer cases 

, HPV screening can also be highly effective in averting deaths from cervical cancer. Screens are low-cost and some can be done at home, so women who do not want to come to the clinic or undergo a cervical examination can still be screened 

Vaccination against HPV virus strains 16 and 18 (those most commonly associated with cervical cancer) is also highly cost-effective in some areas

. These vaccinations are included in the DCP3 recommendations, though not the WHO “Best Buys” list. HPV-16 and -18 are responsible for more than 70% of cervical cancers 

, with HPV-16 detected in 57% of cervical cancers and HPV-18 detected in 17% 

. Along with 6 less common strains, these HPV types are responsible for over 90% of cervical cancer cases.

The HPV vaccine is relatively high-cost and requires two follow-ups, so it’s not cost-effective in all areas. However, heavily subsidised vaccines, such as those offered by GAVI alliance, make vaccination much more cost-effective (vaccines at $5 per dose are available to 37 countries in Sub-Saharan Africa)

The vaccine requires a cold chain, making some areas of sub-Saharan Africa difficult to cover, but it has been estimated that 70% coverage of 9-year old girls for 5 years could avert 670,000 cases of cervical cancer in the region

Included in the DCP3, but not the WHO recommendations, is screening for breast cancer and treatment of early-stage tumours. Since presentation with advanced-stage tumour is more common in low/middle income countries

, examination by medical professionals and education in breast self-awareness may decrease death rates, as treatment earlier in the disease course is easier and has a higher success rate

A case study in Malaysia found that incidence of patients presenting with late stage breast cancer decreased from 77% to 37% after a country-wide drive to increase awareness. As part of the drive, nurses began to visit rural areas to give talks, demonstrate breast awareness and perform examinations

Finally, DCP3 also highlights the cost-effectiveness of treating some childhood cancers. The very high cure rates seen in some childhood cancers in HICs are often dependant on intensive supportive care which is not available in LICs

. However, some studies have shown less intensive treatments of certain cancers to be effective and highly cost-effective, with treatment of Burkitt’s Lymphoma, for instance, costing as little as £500 

Twinning programs, linking hospitals in LICs with specialist hospitals in HICs allow expertise to be shared, improving treatment and survival rates

. The success seen in childhood cancer can act as a strong motivator to encourage governments to pursue cancer treatment programs and give early stage patients the hope required to seek help as soon as they discover symptoms of disease3.

Despite the high cost of cancer in HICs (£5.8bn in the UK in 2010/11 - 5.4% of NHS budget

), affordable changes can be made in LICs which might avert millions of deaths over the coming century. In many cases, prevention is far more cost-effective than treatment. However, perhaps surprisingly, in cases such as cervical cancer, and potentially some childhood cancers, treating early stage disease is also highly cost effective.

For more on effective cancer interventions, see also our 

Can cancer interventions ever be cost-effective?

According to a recent study, they could be.

An NIH-funded paper published earlier this year 

if mothers-to-be had malaria, schistosomiasis, or hookworm infections during their pregnancy, their babies were less well-protected by some vaccines.

 This may help to explain why some vaccines are less effective in areas of developing nations 

In the study, babies were given a vaccination which protects against five diseases – diphtheria, tetanus, pertussis, Hib (a cause of meningitis and septicaemia) and hepatitis B – and the level of protection produced in response to the Hib, hepatitis B, diphtheria and tetanus components were then measured. Parasite infections affected how much protection was given by the Hib and diphtheria components of the vaccine.

For the Hib component, babies from mothers who had been infected with malaria, filariasis or hook-worm gained less protection from the vaccine than those whose mothers did not have those infections. This suggests that the worm infection in the mother reduced the effect of the vaccines in the babies.

The picture gets more complicated when the mother has more than one infection. It has been known for some time that parasites use high level evasion tactics to avoid the immune system, and that this may stop vaccines from working so well

. As an example, BCG vaccinations provide less protection against tuberculosis in people who have a worm burden than those who don’t 

.In their attempts to avoid elimination by the immune system, parasites end up triggering off a range of immunological functions, sometimes with counter-intuitive effects.

For instance, babies whose mothers had malaria had less protection from the Hib vaccine than those whose mothers were malaria-free. Babies whose mothers had worm infection also had less protection. But babies whose mothers had BOTH malaria and worm infection had a better response to the vaccine than those whose mothers only had malaria. So, in this case, the combination of worms and malaria works on the side of the vaccine, making the response less bad.

To make it even more complicated, there is a different response to the part of the vaccine that protects against diphtheria. Here, malaria infection in the mother had little effect, and worm infection in the mother also had little effect, but babies whose mothers suffered from both malaria and worms had a worse response to the vaccine.

So what’s going on here? Why the different response?

Parasites’ tactics include complex communications trickery, signalling the immune system to err towards tolerance rather than aggression. The signals caused by the parasites in pregnant mothers may end up pushing their babies’ immune systems into having a more tolerant and less aggressive response as well. Unfortunately, the processes which are involved in producing an aggressive immune response are important in gaining protection from many vaccines 

The constant balancing act between tolerance and aggression is in part controlled by immune players called Th1 and Th2 cells. Each produces a cocktail of self-interested chemicals to keep its philosophy on top. Once a Th1 response starts, it tends to keep going at the expense of the Th2 response, and vice-versa 

. Any upset to the normal Th1:Th2 balance is likely to make the vaccine response less effective.

Parasites like intestinal worms push for a Th2 response 

, which is less aggressive and more tolerant. But the more aggressive Th1 response is normally what’s required for vaccines to give good protection against diseases.

Malaria is well-known for suppressing the immune system and paralysing vital components to suit its own ends, as well as being hugely damaging to pregnancies, increasing the risk of premature birth, miscarriage, low birth weight and infant mortality 

, so treatment during pregnancy is important 

. However, in this situation, the malaria parasite may be inadvertently causing some immune-system rebalancing. Malaria parasites can infect the placenta, pushing towards a more aggressive, Th1 response in the baby 

 and potentially contributing to re-balancing the Th1:Th2 response. The malaria parasite in the mother may also increase the work of an immune-balancing cell in the baby 

To top off this complex immunological mash-up, material from infections in pregnant mothers doesn’t tend have a hostile reception when it reaches their unborn children. Instead, it causes the production of cells and chemicals designed to avoid immunological warfare between the mother and baby during pregnancy 

. But the result is a calming of the immune system, which doesn’t fit well with good protection from the vaccine.

What does this mean for reducing disease?

The interactions between parasites and the immune system are by no means simple, so predicting what will happen if you remove one of the players is often not straightforward. However, this paper does provide more evidence that 

removal of parasite burden would be a good thing for vaccination efforts. It also shows the importance of considering how different infections interact with each other during pregnancy, and understanding the full implications of channelling resources towards any one particular disease.

The Giving What We Can top charity recommendations currently include organisations devoted to tackling neglected tropical diseases, such as 

, which distributes insecticide-treated mosquito nets. 

Research like this further improves the case for donating to these highly effective charities, highlighting the multi-faceted and potentially surprising effects of parasite infection.

Could parasites be making vaccinations less effective in developing countries?

Juliet has a background in immunology and cancer biology, holding a bachelor's degree from the University of Bristol and a master's degree from the University of Southampton.

Juliet has a background in immunology and cancer biology and master's degree from the University of Southampton.

Juliet Bowater

About

Articles

Can cancer interventions ever be cost-effective?

Could parasites be making vaccinations less effective in developing countries?