HIV infection in older adults in sub-Saharan Africa: extrapolating prevalence from existing data
Joel Negin a & Robert G Cumming a
a. University of Sydney, School of Public Health, Edward Ford Building, Sydney, NSW, 2006, Australia.
Correspondence to Joel Negin (e-mail: email@example.com).
(Submitted: 21 January 2010 – Revised version received: 20 July 2010 – Accepted: 04 August 2010 – Published online: 27 August 2010.)
Bulletin of the World Health Organization 2010;88:847-853. doi: 10.2471/BLT.10.076349
Despite the global attention being paid to the epidemic of infection with the human immunodeficiency virus (HIV), HIV infection rates among older adults in sub-Saharan Africa have been a neglected area of study. The Joint United Nations Programme on HIV/AIDS (UNAIDS) and other prominent sources of data report prevalence rates only for those aged 15–49 years, and the indicators used by the United Nations General Assembly Special Session focus predominantly on the same age group. The burden of disease among those aged ≥ 50 years is almost always ignored and this represents a significant blind spot in the global response to the epidemic of HIV infection and acquired immunodeficiency syndrome (AIDS).
As a result of the situation described above, there is a paucity of data on HIV infection in people aged ≥ 50 years. In 2006, UNAIDS shifted to reporting the number of HIV-positive (HIV+) people aged ≥ 15 years, but it provides limited data specifically on those aged > 49. The 2006 report on the epidemic revealed some of the only existing data for this age group and stated that globally “around 2.8 million adults aged 50 years and older were living with HIV in 2005”.1 Other estimates have been based on limited data.2 While individuals > 49 years of age account for approximately 10% of the cumulative HIV infection case-load in the United States of America,3 the corresponding proportion for Africa is not known.
The few existing studies on HIV infection among older adults have focused mainly on developed countries.4–9 Studies in developing countries emphasize the social and economic impact of HIV infection – mainly its effect on older grandparents in their role as caretakers of children orphaned as a result of parental HIV infection – and have ignored the prevalence of HIV infection in older people and its impact on their lives.10,11
As more people in sub-Saharan Africa have begun taking antiretroviral treatment, mortality rates have dropped12,13 and HIV+ individuals are surviving longer. At the same time, older people remain at risk for infection. In the light of the ageing of the general population, there is a need to better understand the prevalence and characteristics of HIV infection among older adults in sub-Saharan Africa. To begin to address this information gap, we have used existing data and information to estimate the prevalence of HIV infection among people > 49 years of age in sub-Saharan Africa.
The data in this analysis came from a variety of sources. The main source was data on the prevalence of HIV infection released by UNAIDS in conjunction with its 2008 report on the global AIDS epidemic.14 The UNAIDS web site provides data, by country and by year, on the estimated number of people living with HIV as well as on the prevalence of HIV infection among adults aged 15–49 years.14 It does not, however, provide the number of HIV+ people aged ≥ 50 years or the prevalence of HIV infection in this age group. To derive those data, we needed to know the total population of each country in sub-Saharan Africa and its age distribution. We obtained the total population of each country from the 2007 world population data sheet15 and extracted the percentage of the total population aged 15–49 years and ≥ 50 years, by country, from World population prospects: the 2008 revision, using data from 2005, the most recent year for which data were available.16 Using population data from 2007 and the percentage of the total population aged 15–49 years, we calculated the number of people aged 15–49 years in each country. The use of UNAIDS data on the prevalence of HIV infection in this age group allowed us to calculate the number of people that had HIV infection. By subtracting this number from the total number of HIV+ people who were aged ≥ 15 years, as calculated by UNAIDS, we estimated the number of HIV+ people aged ≥ 50 years. We then divided this number by the total number of people aged ≥ 50 in a country (as derived from World population prospects: the 2008 revision) to estimate the prevalence of HIV infection among people aged ≥ 50 years.
For this analysis we used sub-Saharan African countries as classified by UNAIDS. Data were not available for Cape Verde, the Comoros or Sao Tome and Principe. For the Democratic Republic of the Congo UNAIDS only provides high and low estimates of the number of people living with HIV. We used the midpoint between the two. UNAIDS data for Kenya for 2007 were awaiting finalization of the Kenya AIDS Indicator Survey, so we used those results, released in 2009, for analysis.17
Population-based surveys, predominantly the Demographic and Health Surveys (DHS) web site,18 were a second source of data for this study. We accessed the DHS reports and AIDS Indicator Survey reports on the site. To focus on the most recent data, we reviewed all surveys conducted after 2000 that contained information on HIV testing in countries in sub-Saharan Africa, and we extracted relevant data. Of the 43 DHS reports conducted after 2000 in countries in sub-Saharan Africa, 39 (91%) included interviewees aged ≥ 50, but only if they were men, and the upper age limit for these interviewees ranged from 54 to 64 years. Because the surveys are designed primarily to collect data on maternal and child health, the age ceiling for women interviewees is 49 years.
Of the 39 reports that included interviewees aged ≥ 50, 18 provided data on the prevalence of HIV infection based on population-based HIV testing of interviewees in this age group. The others contained information only on HIV-related awareness and behaviour. Of the four AIDS Indicator Surveys for which data were available, only the Ugandan survey included interviewees aged > 49 years: in that country, both men and women aged < 60 years were interviewed.
In addition, we searched the Internet and the grey literature to identify other sources of data on population-based HIV testing in sub-Saharan Africa. South African data sources and the Kenyan AIDS Indicator Survey were identified through this process.
Based on the analysis of data obtained from UNAIDS and World population prospects: the 2008 revision, we estimated that in 2007 approximately 3 million people aged ≥ 50 years were living with HIV in sub-Saharan Africa. This represents 14.3% of the approximately 21 million people aged ≥ 15 years who are infected with HIV (Table 1). The five countries with the highest number of older adults living with HIV in sub-Saharan Africa were Mozambique, Nigeria, South Africa, Zambia and Zimbabwe; together these countries accounted for 54% of the total number of older adults living with HIV. The estimated prevalence of HIV infection among the 74 million people aged ≥ 50 years in sub-Saharan Africa is 4.0%, compared with 5.0% among those aged 15–49 years.
Table 1. Infection with the human immunodeficiency virus (HIV) among adults aged ≥ 50 years (older adults) and people aged 15–49 years in sub-Saharan Africa, by country, 2007
Table 2 presents information on the prevalence of HIV infection among those aged ≥ 50 years in several countries in sub-Saharan Africa from DHS, AIDS Indicator Surveys and other population-based surveys. The highest prevalence of HIV infection among those aged ≥ 50 years was found in Zimbabwe during 2005–2006: 20% of all men aged 50–54 years were living with HIV.22
Table 2. Prevalence of infection with the human immunodeficiency virus (HIV) among older adults (i.e. people aged ≥ 50 years) in sub-Saharan Africa, by country, from population-based surveys conducted after 2000
The 39 DHS reports that include male interviewees aged ≥ 50 also contain data on HIV-related awareness, behaviour and attitudes. The questions asked during the course of the decade included in our study differ and this makes direct comparisons difficult, but for each country the responses of those aged ≥ 50 years can be compared with those of people < 50. In general, older men are less aware of and knowledgeable about HIV-prevention measures than men aged 15–49. Interviewees in eight countries (Benin, Cape Verde, Ghana, Lesotho, Mali, Nigeria, Uganda and Zambia) were asked the same question about whether using a condom and having only one sexual partner are effective prevention measures, and in seven of the countries (all but Ghana) men aged ≥ 50 years knew less than men < 50. For example, in Nigeria 68.6% (2612/3808) of men aged 15–49 knew that using condoms and having only one partner are effective prevention measures, as opposed to only 58.3% (978/1678) of men aged 50–59.23
In four of the seven countries where interviewees were asked about the number of sexual partners they had had during the past 12 months, namely Benin, the Democratic Republic of the Congo, Ghana and Nigeria, men aged ≥ 50 years were more likely to have had two or more sexual partners than those aged 15–49. In each of these four countries, the percentage of men aged ≥ 50 years who had had two or more sexual partners during the previous 12 months and who had used condoms the last time they had engaged in sexual intercourse was much lower than among men aged 15–49. For example, in Ghana only 7.9% (5/64) of the men aged 50–59 years who had engaged in sex with at least two partners over the previous 12 months had used a condom during their last sexual intercourse, compared with 26.2% (120/459) of men aged 15–49.
An analysis of UNAIDS and World population prospects data suggests that approximately 3 million adults aged ≥ 50 years are living with HIV in sub-Saharan Africa. People in this age group account for 14.3% of all HIV+ people ≥ 15 years of age. This study confirms that HIV infection does not affect younger people exclusively.
Comparisons between the two types of data sources used in this study reveal an occasional match between the prevalence of HIV infection estimated from UNAIDS data and the prevalence obtained from population-based HIV testing. For example, in Benin calculations made from UNAIDS data suggest that in 2007 the prevalence of HIV infection among those aged ≥ 50 years was 1.0%; similarly, DHS data for 2006 suggest a prevalence of 1.0% among men aged 50–64.24 However, in other countries there are significant discrepancies. For Lesotho, data derived from UNAIDS statistics suggest a prevalence of 27.8% in 2007 among those aged ≥ 50 years, whereas according to data from the 2004 DHS, prevalence among men aged 50–59 is around 16%.25 These surveys do not measure the same indicator: most DHS data cover men in a limited age range, as previously indicated, while UNAIDS data are for all adults aged ≥ 50 years.
The main results presented in this paper depend on the quality of the data obtained from UNAIDS. These data are derived from mathematical and demographic projection models based primarily on prevalence data from population-based surveys, time–trend prevalence data from antenatal clinics, estimates of the need for antiretroviral treatment and its coverage, mortality rates and total population;26–28 they are not designed specifically to quantify the prevalence of HIV infection among older adults. Consequently, prevalence and case-load calculations from UNAIDS reports represent the best available, but they do not allow derivation of exact population numbers. Population-based surveys of HIV infection prevalence among older adults would provide more reliable and robust data.
A few studies have documented HIV infection among older adults: a study in rural Cameroon showed a prevalence of 2.6% among men and women aged 55–70 years,29 and a study among people admitted to hospital in Dar es Salaam, United Republic of Tanzania, reported a prevalence of 15% among those aged ≥ 55.30 A study in the Congo described 175 cases of HIV infection among people aged ≥ 55 years from 1990 to 1996.31 An 81-year-old male who was HIV+ was identified in an Ethiopian study.32 In general, however, data on HIV infection in older adults in Africa are limited.
Two facets to the issue of HIV positivity among older adults generate particular challenges. One is the occurrence of new cases of HIV infection among older adults and the other is the ageing of the population infected with HIV.33
Previous studies have shown that those who become infected with HIV later in life progress more rapidly towards AIDS and death than those who are infected at a younger age. Justice and Weissman have noted evidence that being older at the time of seroconversion is strongly associated with faster disease progression and shorter survival.34 A study in the United Kingdom of Great Britain and Northern Ireland revealed that those who became infected between the ages of 15 and 34 years had a 10-year survival rate of 72%, compared with 12% of those who seroconverted after the age of 55.35 In 2001, the Collaborative Group on AIDS Incubation and HIV Survival predicted a life expectancy of only four years for people who become infected at age ≥ 65 years.36 A 2001 study in the United States demonstrated that reconstitution of the immune system after initiating antiretroviral treatment was slower in older patients.37
As more people survive longer with HIV, the overall case-load will age and new challenges will arise in sub-Saharan Africa. Older adults have greater comorbidity, experience more side-effects from antiretroviral treatment and hence may be less likely to adhere to treatment.34 The toxicity of antiretroviral therapy, combined with decreased kidney and liver function in older individuals, may lead to treatment difficulties such as drug interactions.38 Studies are needed to better understand the pharmacokinetics of antiretroviral agents in elderly people.39
Common misconceptions about sexual activity among older people remain. A study in Nigeria dismissed older people as no longer being sexually active,40 confirming what Ory et al. called “ageist assumptions about sexual behaviour”.33 These attitudes limit the development of appropriate responses tailored specifically to older adults.
Several factors put older people at a higher risk of becoming infected with HIV. The thinning of the vaginal wall after menopause increases the risk of HIV transmission during sex.41 Practices such as wife inheritance and ritual cleansing, in which a widow is expected to either marry or have sex with relatives of the deceased husband, can increase older women’s exposure to the virus.42 Additionally, many older people are poor and may not be able to afford health services.
Older adults’ access to HIV-related services and information is limited: the UNAIDS update for 2009 stated that “even though the largest share of new infections in many African countries occurs among older heterosexual couples, relatively few prevention programmes have specifically focused on older adults”.43 DHS data suggest that levels of condom use and knowledge about condoms are low among older adults. In the United States, Ory and Mack noted that people aged ≥ 50 years who had known risk factors for HIV infection were one-sixth as likely to report using condoms as people in their twenties with comparable risk factors.3 The lack of targeted prevention services becomes even more important considering that many older people care for younger ones, since a lack of knowledge may prevent older people from effectively teaching the next generation about HIV.
The delivery of services to older adults with HIV infection needs to be improved. In the United States, el-Sadr and Gettler have indicated that health-care providers are less likely to attribute signs and symptoms of disease in older people to HIV infection.44 Data from Brazil suggest that older people are diagnosed later in the course of HIV infection, with more AIDS-defining diseases present at diagnosis.45 This may be true for Africa as well.
South Africa has added men aged ≥ 50 years to its list of populations considered to be at greatest risk for HIV infection, according to a 2008 survey.20 The 6.0% prevalence among these men, together with the limited reach of national communication programmes, low levels of knowledge and poor adoption of preventive behaviours, has highlighted the need to focus prevention on this group.
The need to better understand the various HIV-related challenges faced by older adults will increase as the HIV+ population ages. Research should be aimed at understanding the specific vulnerabilities and challenges faced by this group. It should focus on understanding the impact of highly active antiretroviral therapy on older people in Africa and on understanding the sexual behaviour and practices of older people.
Barnett views HIV infection and AIDS as posing a new type of challenge for the global community: a “long-wave event” whose “troubling and large-scale effects emerge gradually over decades”.46 For the past few decades, the global HIV community has focused on people aged 15–49 years, often ignoring the long-wave elements of the epidemic. A significant percentage of the population – those aged ≥ 50 years – has been largely excluded from HIV prevention and testing services. The high prevalence of HIV infection and the high rates of death from AIDS-related causes among older people in developing countries call for greater efforts to integrate the needs of older people into responses to the HIV epidemic and to strengthen targeted prevention, care and support programmes.
- 2006 report on the global AIDS epidemic. Geneva: Joint United Nations Programme on HIV/AIDS; 2006.
- Knodel J, Watkins S, VanLandingham M. AIDS and older persons: an international perspective. J Acquir Immune Defic Syndr 2003; 33: S153-65 pmid: 12853864.
- Ory MG, Mack KA. Middle-aged and older people with AIDS. Res Aging 1998; 20: 653-64 doi: 10.1177/0164027598206002.
- Orchi N, Balzano R, Scognamiglio P, Navarra A, De Carli G, Elia P, et al., SENDIH group, et al. Ageing with HIV: newly diagnosed older adults in Italy. AIDS Care 2008; 20: 419-25 doi: 10.1080/09540120701867073 pmid: 18449818.
- Bhavan KP, Kampalath VN, Overton ET. The aging of the HIV epidemic. Curr HIV/AIDS Rep 2008; 5: 150-8 doi: 10.1007/s11904-008-0023-3 pmid: 18627664.
- Navarro G, Nogueras MM, Segura F, Casabona J, Miro JM, Murillas J, et al., PISCIS Study Group, et al. HIV-1 infected patients older than 50 years. PISCIS cohort study. J Infect 2008; 57: 64-71 doi: 10.1016/j.jinf.2008.05.003 pmid: 18572247.
- Pitts M, Grierson J, Misson S. Growing older with HIV: a study of health, social and economic circumstances for people Living with HIV in Australia over the age of 50 years. AIDS Patient Care STDS 2005; 19: 460-5 doi: 10.1089/apc.2005.19.460 pmid: 16053403.
- Schmid GP, Williams BG, Garcia-Calleja JM, Miller C, Segar E, Southworth M, et al., et al. The unexplored story of HIV and ageing. Bull World Health Organ 2009; 87: 162-162A doi: 10.2471/BLT.09.064030 pmid: 19377704.
- Elford J, Ibrahim F, Bukutu C, Anderson J. Over fifty and living with HIV in London. Sex Transm Infect 2008; 84: 468-72 doi: 10.1136/sti.2008.031187 pmid: 19028949.
- Kyobutungi C, Ezeh AC, Zulu E, Falkingham J. HIV/AIDS and the health of older people in the slums of Nairobi, Kenya: results from a cross sectional survey. BMC Public Health 2009; 9: 153- doi: 10.1186/1471-2458-9-153 pmid: 19473488.
- Schatz E, Ogunmefun C. Caring and contributing: the role of older women in rural South African multi-generational households in the HIV/AIDS Era. World Dev 2007; 35: 1390-403 doi: 10.1016/j.worlddev.2007.04.004.
- Mermin J, Were W, Ekwaru JP, Moore D, Downing R, Behumbiize P, et al., et al. Mortality in HIV-infected Ugandan adults receiving antiretroviral treatment and survival of their HIV-uninfected children: a prospective cohort study. Lancet 2008; 371: 752-9 doi: 10.1016/S0140-6736(08)60345-1 pmid: 18313504.
- Stover J, Fidzani B, Molomo BC, Moeti T, Musuka G. Estimated HIV trends and program effects in Botswana. PLoS One 2008; 3: e3729- doi: 10.1371/journal.pone.0003729 pmid: 19008957.
- 2008 Report on the global AIDS epidemic. Geneva: Joint United Nations Programme on HIV/AIDS; 2008. Available from: http://www.unaids.org/en/KnowledgeCentre/HIVData/GlobalReport/2008/2008_Global_report.asp. [accessed 20 August 2010].
- Population Reference Bureau. 2007 world population data sheet. Available from: http://www.prb.org/pdf07/07WPDS_Eng.pdf [accessed 20 August 2010].
- World population prospects: the 2008 revision [Internet]. Panel 2: detailed data. Geneva: United Nations Population Division; 2008. Available from: http://esa.un.org/unpp/index.asp?panel=2 [accessed 6 August 2010].
- National AIDS and STD Control Program. Kenya AIDS Indicator Survey 2007 final report. Nairobi: Ministry of Health; 2009.
- Measure DHS. Demographic and Health Surveys [Internet]. Calverton: ICF Macro; 2010. Available from: http://www.measuredhs.com/pubs/browse_region.cfm [accessed 20 August 2010].
- Shisana O, Rehle T, Simbayi L, Mbelle N. South African National HIV Prevalence, Incidence, Behaviour and Communication Survey 2005. Cape Town: South African Medical Research Council; 2005.
- Shisana O, Rehle T, Simbayi LC, Zuma K, Jooste S, Pillay-van-Wyk V, et al. South African National HIV Prevalence, Incidence, Behaviour and Communication Survey 2008: a turning tide among teenagers? Cape Town: HSRC Press; 2009.
- Uganda HIV/AIDS Sero-behavioural Survey 2004–2005. Calverton: Ministry of Health of Uganda & ORC Macro; 2006.
- Zimbabwe Demographic and Health Survey 2005-06. Calverton: Central Statistical Office of Zimbabwe & Macro International; 2007.
- Nigeria Demographic and Health Survey 2008. Abuja: National Population Commission of Nigeria & ICF Macro; 2009.
- Enquête Démographique et de Santé (EDSB-III) – Bénin 2006. Calverton: Institut National de la Statistique et de l’Analyse Économique [Benin] & Macro International; 2007.
- Lesotho Demographic and Health Survey 2004. Calverton: Ministry of Health and Social Welfare of Lesotho, Bureau of Statistics Lesotho & ORC Macro; 2005.
- Stover J. AIM: a computer program for making HIV/AIDS projections and examining the demographic and social impacts of AIDS [computer manual]. Washington: United States Agency for International Development; 2009. Available from: http://data.unaids.org/pub/Manual/2009/20090414_aim_manual_2009_en.pdf [accessed 20 August 2010].
- Stover J, Walker N, Grassly NC, Marston M. Projecting the demographic impact of AIDS and the number of people in need of treatment: updates to the Spectrum projection package. Sex Transm Infect 2006; 82: iii45-50 doi: 10.1136/sti.2006.020172 pmid: 16735293.
- Diaz T, Garcia-Calleja JM, Ghys PD, Sabin K. Advances and future directions in HIV surveillance in low- and middle-income countries. Curr Opin HIV AIDS 2009; 4: 253-9 doi: 10.1097/COH.0b013e32832c1898 pmid: 19532061.
- Nyambi P, Zekeng L, Kenfack H, Tongo M, Nanfack A, Nkombe I, et al., et al. HIV infection in rural villages of Cameroon. J Acquir Immune Defic Syndr 2002; 31: 506-13 pmid: 12473839.
- Mtei LN, Pallangyo KP. HIV infection in elderly medical patients. East Afr Med J 2001; 78: 144-7 pmid: 12002055.
- Ibara JR, Itoua C, Gathse A, Obengui , Gassaye D, Nkoua JL, et al., et al. Le syndrome d'immunodéficience acquise (sida) chez les personnes âgées en zone tropicale. À propos de 175 cas congolais [Acquired immunodeficiency syndrome in elderly persons in a tropical zone. Apropros of 175 cases in the Congo]. Bull Soc Pathol Exot 2002; 95: 100-2 pmid: 12145951.
- Kassu A, Mekonnen A, Bekele A, Abseno N, Melese E, Moges F, et al., et al. HIV and syphilis infection among elderly people in northwest Ethiopia. Jpn J Infect Dis 2004; 57: 264-7 pmid: 15623952.
- Ory MG, Zablotsky DL, Crystal S. HIV/AIDS and aging: identifying a prevention research and care agenda. Res Aging 1998; 20: 637-52 doi: 10.1177/0164027598206001.
- Justice AC, Weissman S. The survival experience of older and younger adults with AIDS: is there a growing gap in survival? Res Aging 1998; 20: 665-85 doi: 10.1177/0164027598206003.
- Darby SC, Ewart DW, Giangrande PLF, Spooner RJD, Rizza CR. Importance of age at infection with HIV-1 for survival and development of AIDS in United Kingdom haemophilia population. UK Haemophilia Centre Directors’ Organisation. Lancet 1996; 347: 1573-9 pmid: 8667864.
- Collaborative Group on AIDS Incubation and HIV Survivaland including the CASCADE EU Concerted Action. Time from HIV-1 seroconversion to AIDS and death before widespread use of highly-active anti-retroviral therapy. A collaborative analysis. Lancet 2000; 355: 1131-7 doi: 10.1016/S0140-6736(00)02061-4 pmid: 10791375.
- Goetz MB, Boscardin WJ, Wiley D, Alkasspooles S. Decreased recovery of CD4 lymphocytes in older HIV-infected patients beginning highly active antiretroviral therapy. AIDS 2001; 15: 1576-9 doi: 10.1097/00002030-200108170-00017 pmid: 11504992.
- Gebo KA. Epidemiology of HIV and response to antiretroviral therapy in the middle aged and elderly. Aging health 2008; 4: 615-27 doi: 10.2217/1745509X.4.6.615 pmid: 19915688.
- Rhee MS, Greenblatt DJ. Pharmacologic consideration for the use of antiretroviral agents in the elderly. J Clin Pharmacol 2008; 48: 1212-25 doi: 10.1177/0091270008322177 pmid: 18812611.
- Akanji BO, Ogunniyi A, Baiyewu O. Healthcare for older persons, a country profile: Nigeria. J Am Geriatr Soc 2002; 50: 1289-92 doi: 10.1046/j.1532-5415.2002.50319.x pmid: 12133027.
- Drew O, Sherrard J. Sexually transmitted infections in the older woman. Menopause Int 2008; 14: 134-5 doi: 10.1258/mi.2008.008020 pmid: 18714080.
- Zaba B, Todd J, Biraro S, Shafer LA, Lutalo T, Ndyanabo A, et al. Diverse age patterns of HIV incidence rates in Africa. Presentation at: XVII International AIDS Conference, Mexico City, 5 August 2008.
- AIDS epidemic update: December 2009. Geneva: Joint United Nations Programme on HIV/AIDS; 2009.
- el-Sadr W, Gettler J. Unrecognized human immunodeficiency virus infection in the elderly. Arch Intern Med 1995; 155: 184-6 doi: 10.1001/archinte.155.2.184 pmid: 7811128.
- Lacerda HR, Kitner D. Mortality of the elderly is still exceedingly high at diagnosis of AIDS despite favourable outcomes after highly active antiretroviral therapy in Recife, Brazil. Int J STD AIDS 2008; 19: 450-4 doi: 10.1258/ijsa.2008.007317 pmid: 18574115.
- Barnett T. A long-wave event: HIV/AIDS, politics, governance and 'security': sundering the intergenerational bond? Int Aff 2006; 82: 297-313 doi: 10.1111/j.1468-2346.2006.00532.x.