Hall, Andrew J

Wild, Christopher P

LSHTM Research Online

Hall, AJ; Wild, CP (2003) Liver cancer in low and middle incomecountries - Prevention should target vaccination, contaminated nee-dles, and aflatoxins. BMJ (Clinical research ed), 326 (7397). pp.994-995. ISSN 0959-8138 DOI: 10.1136/bmj.326.7397.994Downloaded from: http://researchonline.lshtm.ac.uk/16775/DOI: 10.1136/bmj.326.7397.994Usage GuidelinesPlease refer to usage guidelines at http://researchonline.lshtm.ac.uk/policies.html or alterna-tively contact researchonline@lshtm.ac.uk.Available under license: Creative Commons Attribution Non-commercialhttp://creativecommons.org/licenses/by-nc/2.5/that they are useful (a) in identifying the organism inwomen with symptoms but a negative potassiumhydroxide test, particularly if empirical treatmentaimed at uncomplicated vulvovaginal candidiasis hasalready failed, and (b) before embarking on long termsuppressive antifungal treatment.10Jeanne Marrazzo medical directorHarborview Medical Center, Seattle, WA 98104 US(jm2@washington.edu)Competing interests: JM has received research funding andhonoraria for speaking from Pfizer Inc, who make Diflucan.1 Consumer Health Care Products Association.www.chpa-info.org/(accessed 25 Mar 2003).2 Ferris DG, Dekle C, Litaker MS. Women’s use of over-the-counterantifungal medications for gynecologic symptoms. J Fam Pract1996;42:595-600.3 De Leon EM, Jacober SJ, Sobel JD, Foxman B. Prevalence and risk factorsfor vaginal Candida colonization in women with type 1 and type 2diabetes. BMC Infect Dis 2002;2:1.4 Sobel JD, Faro S, Force RW, Foxman B, Ledger WJ, Nyirjesy PR, et al. Vul-vovaginal candidiasis: epidemiologic, diagnostic, and therapeutic consid-erations. Am J Obstet Gynecol 1998;178:203-11.5 Sobel JD. Pathogenesis of recurrent vulvovaginal candidiasis. Curr InfectDis Rep 2002;4:514-9.6 Sobel JD, Kapernick PS, Zervos M, Reed BD, Hooton T, Soper D, et al.Treatment of complicated Candida vaginitis: comparison of single andsequential doses of fluconazole. Am J Obstet Gynecol 2001;185:363-9.7 Reed BD, Gorenflo DW, Gillespie BW, Pierson CL, Zazove P. Sexualbehavior and other risk factors for Candida vulvovaginitis. J Women’sHealth Gend Based Med 2000;9:645-55.8 Watson MC, Grimshaw JM, Bond CM, Mollison J, Ludbrook A. Oralversus intra-vaginal imidazole and triazole anti-fungal treatment ofuncomplicated vulvovaginal candidiasis (thrush). Cochrane Database SystRev 2001;4:CD002845.9 European STD guidelines. Sex Transm Infect 2001;12(suppl 3):73-7.10 Centers for Disease Control and Prevention. Sexually transmitteddiseases treatment guidelines 2002. Morb Mortal Wkly Rep MMWR2002;51(RR-6).11 Geiger AM, Foxman B, Sobel JD. Chronic vulvovaginal candidiasis: char-acteristics of women with Candida albicans, C glabrata, and no Candida.Genitourin Med 1995;71:304-7.12 Eckert LO, Hawes SE, Stevens CE, Koutsky LA, Eschenbach DE, HolmesKK. Vulvovaginal candidiasis: clinical manifestations, risk factors,management algorithm.Obstet Gynecol 1998;92:757-65.Liver cancer in low and middle income countriesPrevention should target vaccination, contaminated needles, and aflatoxinsHepatocellular carcinoma affects more than500 000 people globally annually, and five yearmortality exceeds 95%.More than half of thesepeople are in China, and the incidence in sub-SaharanAfrica is also high.1 The causes of most of these cancersare now known, and their prevention is possible.More than 50% of hepatocellular carcinomas aredue to persistent (as opposed to transient) hepatitis Binfection, and around 25% are due to persistent hepa-titis C virus.2 However, persistent hepatitis B infectionoccurs primarily as a result of infection in the first fiveyears of life, whereas most hepatitis C infection occursin adult life. Thus primary liver cancer in younger indi-viduals (under 50 years of age) is attributable to hepati-tis B in more than 75% of the patients.Aflatoxins are fungal toxins that commonlycontaminate maize, groundnuts, and other crops. Theyplay an important part in modifying the risk of livercancer associated with hepatitis B. After being metabo-lised in the liver the toxin can bind to guanine in DNA,resulting in mutations—for example in codon 249 ofthe TP53 tumour suppressor gene. This mutation iscommon in primary liver cancers from areas of highexposure to aflatoxin, which provides evidence of acarcinogenic role for the toxin.3 The effect of combinedexposure to persistent hepatitis B infection and dietaryaflatoxin has been shown best in a cohort study inChina.4 In that study the risk of liver cancer associatedwith hepatitis B alone was a sevenfold increase overbackground, but the combination of hepatitis B andaflatoxin increased this to a 60-fold risk.Preventing infection with these two hepatitisviruses is one key strategy to reduce the burden of livercancer. Hepatitis B vaccination in infancy has beenshown dramatically to reduce persistent infection, withvaccine efficacy against persistent infection of 94% at 9years of age.5 In Taiwan vaccination has beenassociated with a decline in primary liver cancer in theyoungest age group, which is difficult to explain otherthan through an effect of vaccination.6 The criticalissue is that the child is protected for the first five yearsof life when the risk of persistent infection is high. Evenif protection subsequently wanes only a small numberof persistent infections will result.Although hepatitis B vaccine was first licensed foruse in 1982, the global use of the vaccine has beenincredibly low. This was partly as a result of the initialhigh cost but also because of the lack of political will touse a vaccine that would not have effects for at least twodecades. The development of a global vaccine fund hastransformed this situation. Through the global alliancefor vaccines and immunisation this fund is used tointroduce new and underused vaccines, includinghepatitis B, into the poorest countries of the world. Ifthe strategy proves financially sustainable (responsibil-ity for securing funding for vaccines shifts onto thecountries in the period 2005-10) then futuregenerations will be spared liver cancer.No vaccine is yet available for hepatitis C. Since themajor mode of transmission of this agent is bycontaminated needles the key strategy to prevent per-sistent infection is by public health programmes forsafe injection. The World Health Organization recentlylaunched the safe injection global network (SIGN) tothis end.7 Again, if it is successful much liver cancer inthe older age groups will be prevented.Prevention of infection with hepatitis B and C isnow promising but by its nature has to be a long termstrategy. At the same time there are some 350 millioncarriers of hepatitis B virus in the world who continueat high risk of cancer. What can we do for them?This is where aflatoxin is important. We can poten-tially modify risk by reducing or eliminating exposure.8At an individual level this can be done by modifyingdiet—but this is not an option for many of the affectedpoor rural communities. Chemopreventive agents (forexample, oltipraz and chlorophyllin), which reduce theburden of harmful aflatoxin metabolites in the body,have been studied.9 Although of potential in targetedindividuals, this is unlikely to be a viable public healthEditorialsBMJ 2003;326:994–5994 BMJ VOLUME 326 10 MAY 2003 bmj.comoption for China and Africa. In contrast severalagricultural strategies reduce the quantity of aflatoxinin food. Genetic modification of crops to enhance fun-gal resistance is a promising method and biocontrol byflooding fields with non-toxigenic fungi is another. Butmuch of the contamination of food occurs after theharvest and during storage. Methods to reduce humid-ity can limit fungal growth. Drying the crop in the sun,on a mat, discarding visibly mouldy kernels or nutsbefore storage, and using natural fibre sacks for storageand placing these on wooden pallets to keep the cropdry can be very effective.8 10 Rural communities can usethese techniques at minimal expense. We urgentlyneed to evaluate their impact on human exposure toaflatoxin and implement them for the benefit of exist-ing hepatitis B carriers—who make up 15-20% of manypopulations at high risk.Andrew J Hall professor of epidemiologyLondon School of Hygiene and Tropical Medicine, LondonWC1E 7HT (andy.hall@lshtm.ac.uk)Christopher P Wild professor of molecular epidemiologyUniversity of Leeds, Leeds LS2 9JT (c.p.wild@leeds.ac.uk)Competing interests: None declared.1 Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol2001;2:533-43.2 Pisani P, Parkin DM,Munoz N, Ferlay J. Cancer and infection: estimates ofthe attributable fraction in 1990. Cancer Epidemiol Biomarkers Prev1997;6:387-400.3 International Agency for Research on Cancer. IARC monographs on theevaluation of carcinogenic risks to humans. Vol 82: Some traditional herbalmedicines, some mycotoxins,naphthalene and styrene. Lyons: IARC Press, 2002.4 Qian GS, Ross RK, Yu MC, Yuan JM, Gao YT, Henderson BE, et al. Afollow-up study of urinary markers of aflatoxin exposure and liver cancerrisk in Shanghai, Peoples Republic of China. Cancer Epidemiol BiomarkersPrev 1994;3:3-10.5 Viviani S, Jack A, Hall AJ, Maine N, Mendy M, Montesano R, et al. Hepa-titis B vaccination in infancy in The Gambia: protection against carriageat 9 years of age. Vaccine 1999;17:2946-50.6 Chang MH, Chen CJ, Lai MS, Hsu HM,Wu TC, Kong MS, et al. Universalhepatitis B vaccination in Taiwan and the incidence of hepatocellular car-cinoma in children. Taiwan Childhood Hepatoma Study Group. N Engl JMed 1997;336:1855-9.7 World Health Organization. Safe injection global network (SIGN).www.who.int/bct/Main_areas_of_work/SIGN/SIGN.htm (accessed 16Apr 2003).8 Wild CP, Hall AJ. Primary prevention of hepatocellular carcinoma indeveloping countries. Mutat Res 2000;462:381-33.9 Kensler TW, Egner PA, Wang JB, Zhu YR, Zhang BC, Qian GS, et al.Strategies for chemoprevention of liver cancer. Eur J Cancer Prev2002;11(suppl 2): S58-64.10 Turner PC, Sylla A, Diallo MS, Castegnaro JJ, Hall AJ, Wild CP. The roleof aflatoxins and hepatitis viruses in the etiopathogenesis of hepatocellu-lar carcinoma: A basis for primary prevention in Guinea-Conakry, WestAfrica. J Gastroenterol Hepatol, 2002;17(suppl):S441-8.Safety and efficacy of combination vaccinesCombinations reduce distress and are efficacious and safeFor 130 years or more after Jenner introduced avaccine for smallpox this was the only vaccine ingeneral use. Ten vaccines are now included inthe routine childhood vaccination programme in theUnited Kingdom , with multiple doses of most. The useof combination vaccines reduces distress to the recipi-ents and is likely to increase uptake rates. Many combi-nations are as efficacious as the separate vaccines, butthe increasing number of antigens could theoreticallypose problems in terms of reduced immunogenicity orincreased reactogenicity.Good post-marketing surveillance will becomeimportant in monitoring both the clinical efficacy ofcombination vaccines and adverse effects. With respectto clinical efficacy this may be a particular problemwith combination conjugate vaccines. Using combina-tion vaccines in the routine childhood programme inthe United Kingdom amounts to giving 11 injections(24 in the United States), whereas, if given separately,27 (almost 70 in the United States) would be needed.The alternative approaches are combining as manyantigens into as few injections as possible, giving multi-ple simultaneous injections, or giving the required vac-cines over several visits. Generally parents tend to havefewer concerns than health professionals about multi-ple injections.1 2 However, it would seem cruel to givemore injections than required. In addition, if manyinjections are due at the same time, some may bedelayed or not given at all.3 Pentavalent vaccines suchas diphtheria, tetanus, wholecell pertussis vaccine(DTwP), Haemophilus influenzae type B (Hib) vaccine,and inactivated polio vaccine (IPV) are widely available.Hexavalent vaccines such as diphtheria, tetanus, acellu-lar pertussis vaccine (DTaP), hepatitis B virus (HBV)vaccine, IPV, and Hib are being developed.The safety, efficacy, and immunogenicity of a com-bined vaccine may be affected by interactions, not onlybetween the antigens but also between these and othercomponents such as adjuvants, stabilisers, and pre-servatives. Research on combination vaccines is moredifficult than on single antigen vaccines because theyare often replacing widely used single vaccines, makingtrials with placebos unethical. The disease may nolonger be common, so the production of antibodies orimmunogenicity, rather than protection from disease(clinical efficacy), has to be assessed. This may be satis-factory when antibody concentrations correlate closelywith protection, but for some diseases (for example,pertussis) this is not the case. Thus post-marketing sur-veillance is essential.Combining vaccines into one product does notincrease the overall rate of adverse events, and withsome combinations, such as DTaP, the rates are lowerthan when the component vaccines are given sepa-rately.4 Schmitt et al compared antibody responses inchildren receiving DTaP-HBV-IPV-Hib as one injectionwith children receiving the same antigens but with theHib given at a different site. No difference was found inadverse events associated with the different regimens.5In 1998 a paper in the Lancet was interpreted asshowing a link between measles, mumps, and rubellavaccine and pervasive developmental disorder andbowel disease,6 even though the authors said they hadnot proved such a link. Subsequent research has failedto find evidence for this link 7 The suggestedmechanism behind the hypothesis was that combiningantigens produced an unpredictable response. Someparents are concerned that multiple antigens mayoverload the infant’s immune system. A recent reviewset in context the antigenic load from vaccines in com-EditorialsBMJ 2003;326:995–6995BMJ VOLUME 326 10 MAY 2003 bmj.com

Liver cancer in low and middle income countries.

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Liver cancer in low and middle income countries.

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