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Keywords:

  • human papillomavirus;
  • cervical cancer;
  • HIV;
  • sub-Saharan Africa;
  • cervical screening;
  • HPV vaccine
  • papillomavirus humain;
  • cancer cervical;
  • VIH;
  • Afrique sub-saharienne;
  • dépistage du cancer cervical;
  • vaccin anti-HPV
  • Virus del papiloma humano;
  • cáncer de cervix;
  • VIH;
  • África sub-Sahariana;
  • tamizaje cervical;
  • vacuna VPH

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Conclusions
  7. References

Objectives  To identify the gaps of knowledge and highlight the challenges and opportunities for controlling cervical cancer in sub-Saharan Africa (SSA).

Methods  A comprehensive review of peer-reviewed literature to summarize the epidemiological data on human papillomavirus (HPV) and invasive cervical cancer (ICC) by HIV status, to review feasible and effective cervical screening strategies, and to identify barriers in the introduction of HPV vaccination in SSA.

Results  ICC incidence in SSA is one of the highest in the world with an age-standardized incidence rate of 31.0 per 100 000 women. The prevalence of HPV16/18, the two vaccine preventable-types, among women with ICC, does not appear to differ by HIV status on a small case series. However, there are limited data on the role of HIV in the natural history of HPV infection in SSA. Cervical screening coverage ranges from 2.0% to 20.2% in urban areas and 0.4% to 14.0% in rural areas. There are few large scale initiatives to introduce population-based screening using cytology, visual inspection or HPV testing. Only one vaccine safety and immunogenicity study is being conducted in Senegal and Tanzania. Few data are available on vaccine acceptability, health systems preparedness and vaccine cost-effectiveness and long-term impact.

Conclusions  Additional data are needed to strengthen ICC as a public health priority to introduce, implement and sustain effective cervical cancer control in Africa.

Objectifs:  Identifier les lacunes dans les connaissances et mettre en évidence les défis et opportunités de lutte contre le cancer du col utérin en Afrique sub-saharienne (ASS).

Méthodes:  Analyse détaillée de la littérature scientifique afin de rassembler les données épidémiologiques sur le papillomavirus humain (HPV) et le cancer invasif du col utérin (CICU) selon le statut VIH, examiner les stratégies applicables et efficaces de dépistage du cancer du col utérin et identifier les obstacles à l’introduction de la vaccination contre le HVP en ASS.

Résultats:  l’incidence du CICU en ASS est l’une des plus élevées au monde, avec un taux d’incidence normalisé pour l’âge, de 31,0 pour 100 000 femmes. La prévalence de HPV 16/18, les deux types évitables par la vaccination, chez les femmes avec CICU, ne semble pas différer selon le statut VIH sur une petite série de cas. Toutefois, il existe peu de données sur le rôle du VIH dans l’histoire naturelle de l’infection par le HVP en ASS. La couverture du dépistage du cancer du col de l’utérus varie de 2,0%à 20,2% dans les zones urbaines et de 0,4%à 14,0% dans les zones rurales. Il y a peu d’initiatives de grande échelle visant à introduire le dépistage basé sur la population en utilisant la cytologie, l’inspection visuelle ou un test HPV. La seule étude sur la sécurité et l’immunogénicité d’un vaccin est actuellement menée au Sénégal et en Tanzanie. Peu de données sont disponibles sur l’acceptabilité du vaccin, la préparation des systèmes de santé, le rapport coût-efficacité du vaccin et l’impact à long terme.

Conclusions:  Des données supplémentaires sont nécessaires pour renforcer l’introduction du CICU comme une priorité de santé publique, la mise en œuvre et le soutien efficace de la lutte contre le cancer du col de l’utérus en Afrique.

Objetivos:  Identificar las lagunas de conocimiento y subrayar los retos y oportunidades para controlar el cáncer cervical en África sub-Sahariana (ASS).

Métodos:  Revisión de literatura publicada en revistas evaluadas por pares (“peer-reviewed”) para recopilar y resumir los datos epidemiológicos existentes sobre el virus del papiloma humano (VPH) y el cáncer invasivo de cervix (CIC), según el estatus de VIH, con el fin de revisar las estrategias para el tamizaje de cervix realizables y efectivas, e identificar las barreras existentes para la introducción de la vacunación frente a VPH en ASS.

Resultados:  La incidencia de CIC en ASS es una de las más altas en el mundo, con una tasa de incidencia estandarizada por edad de 31.0 por 100,000 mujeres. La prevalencia de VPH 16/18, los dos tipos prevenibles incluidos en la vacuna, entre mujeres con CIC, no parece diferir según el estatus de VIH al mirarlo a pequeña escala. Sin embargo, hay datos limitados sobre el papel del VIH en la historia natural de la infección por VPH en ASS. La cobertura del tamizaje de cervix está entre el 2.0% y el 20.2% en áreas urbanas y entre el 0.4% y el 14.0% en áreas rurales. Hay pocas iniciativas a gran escala para introducir un tamizaje basado en la población utilizando citología, inspección visual o prueba para VPH. Solo se ha realizado un estudio sobre seguridad e inmunogenicidad de la vacuna en Senegal y Tanzania. Existen pocos datos disponibles sobre la aceptación que podría tener la vacuna, la preparación de los sistemas sanitarios, la costo-efectividad de la vacuna y el impacto a largo plazo.

Conclusiones:  Se requieren datos adicionales para fortalecer el CIC como una prioridad de salud pública e introducir, implementar y mantener un control de cáncer de cervix efectivo en África.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Conclusions
  7. References

Cancer of the cervix uteri is the most common cancer among women in sub-Saharan Africa (SSA). The magnitude of the problem has been under-recognized and under-prioritized compared to competing health priorities such as HIV/AIDS, tuberculosis and malaria. This is due to lack of epidemiological data and poor awareness, lack of human and financial resources, non-existent cancer service policies and lack of political will to address the complex problem (Denny et al. 2006; Parkin et al. 2008).

Organized screening and early treatment programmes have been effective in preventing cervical cancer in industrialized countries but they are costly and difficult to implement in resource-constrained settings. Despite our understanding of the causal relationship of the human papillomavirus (HPV) and cervical cancer (Bosch et al. 2002) and the availability of effective HPV vaccines to prevent infection and disease (Schiller et al. 2008), the opportunity of these vaccines to have an effective impact in SSA will not materialize until they become affordable and integrated within the framework of national immunization programmes (Kane et al. 2006). Until then, cervical cancer prevention will rely on secondary prevention measures.

This review aims to summarize the current epidemiology of HPV and cervical cancer and the complexity of implementing prevention in sub-Saharan Africa; to identify gaps of knowledge and to highlight the challenges and opportunities for controlling cervical cancer in the region.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Conclusions
  7. References

We conducted a comprehensive review of peer-reviewed literature in databases of the World Health Organization and Institut Catalá d’Oncologia (WHO/ICO) Information Centre on HPV and Cervical Cancer (http://www.who.int/hpvcentre), the International Agency for Research on Cancer (IARC) Screening Group (http://www.screening.iarc.fr), PubMed/MEDLINE, and reports from the World Health Organization (WHO). The following medical subject heading (MESH) and text words were used alone or in combination: ‘HPV’, ‘cervical cancer’, ‘cervical screening’, ‘HPV vaccination’ and ‘sub-Saharan Africa’. This review summarizes the evidence from recent systematic reviews, meta-analyses, narrative reviews (non-systematic reviews), epidemiological studies, modelling and related analyses and practice guidelines.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Conclusions
  7. References

Cervical cancer in sub-Saharan Africa

An estimated number of 70 722 new cases of invasive cervical cancer (ICC) occur annually in sub-Saharan Africa and it is responsible for one-quarter of all female cancers (Parkin et al. 2008). ICC incidence in sub-Saharan Africa is one of the highest in the world with an estimated overall age-standardized incidence rate (ASR) of 31 per 100 000 women and varies by region with 42.7 in East Africa, 38.2 in Southern Africa, 28 in Central Africa and 29.3 in Western Africa (Figure 1) (Ferlay et al. 2004; Parkin & Bray 2006). In contrast, the ASR is 12.1 in Northern Africa and 11.9 in Europe (Parkin et al. 2008). However, better cancer incidence data are needed to characterize the burden of disease. At present, only a few population-based cancer registries exist in Africa, covering 11% of the population, and fewer produce high quality incidence data (Parkin et al. 2008). In the period 1998–2002, only two cancer registries in the region, Kyadondo County in Uganda and Harare in Zimbabwe, produced high quality data and reported ASR of 45.8 and 47.3 per 100 000, respectively (Curado et al. 2007).

image

Figure 1.  Age-standardised (world) incidence rates of cervical cancer (Ferlay J et al. 2002) and HIV prevalence (UNAIDS, 2008) in Africa.

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It remains unclear whether the HIV epidemic (Figure 1) has affected the incidence of ICC in sub-Saharan Africa as incidence rates appear to have remained unchanged between the 1960s and 1990s as seen in Nigeria and South Africa or increasing in Bulawayo, Zimbabwe and Kampala, Uganda (Parkin et al. 2008). Furthermore, it is unknown whether more effective AIDS control interventions, such as better access to antiretroviral treatment (ART) will reduce the incidence of ICC because of immune reconstitution or increase the incidence as a result of longer life expectancy and potential risk for disease progression. It is projected that, irrespective of changing risk, population growth and ageing, the likely future burden of cervical cancer in sub-Saharan Africa will rise to about 118 000 new cases in 2025, which is a 67% increase from 2002 (Ferlay et al. 2004).

Epidemiology of HPV infection and ICC

Among the 15 high-risk (HR) oncogenic HPV genotypes that have been identified, HPV16 and 18, the two vaccine-preventable types, show a greater risk of progression to pre-cancerous lesions than other HR types (Khan et al. 2005; Schiffman et al. 2005). In designing effective prevention strategies, HPV type-specific data are therefore essential to estimating the impact of HPV vaccines and cervical cancer screening.

Burden of HPV prevalence and type-distribution in the general population

Cross-sectional studies have shown that the overall prevalence of any HPV type in the general populations of sub-Saharan Africa for women with normal cytology is 21.8% (HPV Information Centre 2009). The prevalence of HPV types 16 and 18 among ICC cases ranges from 43.7% in Senegal to 90.2% in Ethiopia (Table 1) (HPV Information Centre 2009). The overall combined estimate of HPV16/18 prevalence among ICC cases in sub-Saharan Africa is 69.2%, which is consistent with the worldwide estimate of 70% (HPV Information Centre 2009).

Table 1.   HPV16/18 prevalence in cases of invasive cervical cancer (ICC) from published studies in sub-Saharan Africa, according to HIV status
CountryNo. of women with ICC testedHPV16/18 Prevalence, % (95% CI*)
  1. a Estimates from HPV Information Centre, 2009.

  2. b Estimates from De Vuyst et al., 2008.

  3. c Estimates from Sahasrabuddhe et al., 2007.

  4. *CI, confidence interval.

HIV-negative womena
 Benin666.7 (28.9–100.0)
 Guinea1844.4 (21.5–67.4)
 Ethiopia16390.2 (85.6–94.8)
 Kenya26160.9 (55.0–66-8)
 Mozambique30279.1 (74.6–83.7)
 Mali12354.5 (45.7–63.3)
 Senegal7143.7 (32.1–55.2)
 South Africa30762.9 (57.5–68.3)
 Tanzania10272.6 (63.9–81.2)
 Uganda15474.0 (67.1–81.0)
 Zimbabwe9879.6 (71.6–87.6)
 Total 1605 69.2 (66.9–71.4)
HIV-positive women
 Kenyab5168.6 (55.9–81.4)
 Zambiac2853.6 (35.1–72.0)
 Total 79 63.3 (52.7–73.9)

Figure 2 shows the five most common HR HPV types among women with normal cytology, squamous intraepithelial lesions (SIL) and ICC in the general population of sub-Saharan Africa from a meta-analysis (HPV Information Centre 2009). The five most frequent HPV types among women with ICC according to ranking order are HPV 16, 18, 45, 33 and 35, a distribution which does not differ significantly from the worldwide distribution (HPV 16, 18, 33, 45 and 31) (HPV Information Centre 2009). An ongoing international survey using a centralized HPV testing and pathology laboratory to evaluate a collection of 10 000 archived cervical cancer tissue samples worldwide confirmed a similar distribution for the sub-Saharan Africa region although this only included samples from three countries, Mozambique, Nigeria and Uganda (de Sanjose et al. 2009).

image

Figure 2.  The five most frequent high-risk HPV types among women in the general population with normal cytology, low-grade intraepithelial lesions (LSIL), high-grade intraepithelial lesions (HSIL), and invasive cervical cancer (ICC) in sub-Saharan Africa [HPV Information Centre, 2009].

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While HPV prevalence and type-distribution have been aggregated and summarized for the vast region of sub-Saharan Africa, there are, however, large gaps in this epidemiological picture with virtually no data available for Central African countries, and a paucity of country-specific data in some sub-regions. These data would ideally be required to better understand factors influencing local epidemiology of ICC and to predict the local impact of vaccines.

Sexual and reproductive behaviour and risk of HPV infection and cervical carcinogenesis

Early age at first sexual intercourse (AFSI) and early pregnancy have been identified as risk factors for ICC in developing countries (Louie et al. 2009). AFSI is an important determinant of exposure to HPV infection and pregnancy as a determinant of risk for ICC, particularly in those who are highly parous (Louie et al. 2009). This is highly relevant in the African context, in which young women initiate these two events at an early age and experience high parity. Data on selected sexual and reproductive health factors are shown in Table 2 as proxy measures that could be used to inform on cervical cancer prevention strategies (i.e. appropriate age for HPV vaccination). Median AFSI for girls ranges from 15 to 20 years and total fertility ranges from 1.9 to 6.9 in sub-Saharan Africa. Condom use is not often reported by young African women except for non-barrier methods of contraception (Cleland et al. 2006). If unprotected sex is practiced, uncircumcized men with a history of multiple sexual partners, in particular, may increase the risk of cervical cancer in their female partners (Castellsague et al. 2002).

Table 2.   Potential target HPV vaccine populations and selected sexual and reproductive health, HIV, education and immunisation indicators in sub-Saharan Africa
 Total population, Women (thousands)aWomen Aged 10-14 (thousands)aWomen Aged 15-24 (thousands)a Age at first sexual intercoursebTotal FertilitybEstimated number of women 15+ years living with HIV (thousands)dCervical Screening Coverage, %c,eNet primary school enrolment ratio (%)c, fVaccine coverage (%) 2007 of DTP (3rd dose)g
FemaleMaleUrbanRural
  1. aPopulation in 2005. World population prospects: the 2008 revision. New York, Population Division, Department ot Economic and Social Attairs, United Nations Secretariat, 2009.

  2. bMedian age at first sexual intercourse [Wellings et al., 2006].

  3. cWorld fertility patterns 2007. New York, Population Division, Department of Economic and Social Affairs, United Nations Secretariat, 2008.

  4. d2008 Report on the global AIDS epidemic, UNAIDS/WHO, July 2008. [UNAIDS, 2008].

  5. eProportion of females aged 18-69 years who self-reported a pap smear test in the last 3 years [WHO, 2002].

  6. fNet primary school enrolment is the number of boys and girls of primary-school-age that are enrolled in primary education, expressed as a percentage of the total population in that age group. It shows the extent of participation in primary education of children beloing to the official age group corresponding to primary education in the given country. UNESCO Institute for Statistics Data Centre [online database]. Montreal, UNESCO Institute for Statistics, 2007 (http://stats.uis.unesco.org, accessed 28 Jan 2009). gWHO/UNICEF coverage estimates for 1980-2007, as of August 2008. http://www.who.int/inmiunization_monitormg/routine/immunization_coverage/en/index4html.

  7. hPercentage of Total population in sub-Saharan Africa.

Central Africa
 Angola8426108816706.911083
 Cameroon89281107186215.518.85.230082
 Central African   15.517.5 91  
 Republic2089248416  5.2   54
 Chad504562998215.518.56.61109.54.04920
 Congo17132103564.74320.214.05880
 DRC Congo29828385357867.387
 Equator. Guinea30738565.668333
 Gabon6878613815.517.54.3278838
 Sao Tome and      
 Principe771018  4.7   9597
West Africa
 Benin391248034617.517.55.8376967
 Burkina Faso689686163617.520.56.2617.85.13999
 Cape Verde25032254.28981
 Cote d’lvoire9402116889015.518.54.72506.93.14976
 The Gambia77091656.057290
 Ghana108121292102517.519.54.61503.22.26494
 Guinea456556140615.517.55.6486375
 Guinea-Bissau74386616.893763
 Liberia16802051525.2195888
 Mali599275856715.519.56.9567.63.45268
 Mauritania14741741394.644.51.07975
 Niger654882257120.57.1173639
 Nigeria703818535663215.520.55.714005954
 Senegal568173054315.520.55.2386.86.96894
 Sierra Leone26263032486.63064
 Togo302837129215.55.4697288
East Africa
 Burundi37764878575.6535574
 Comoros307346718.55.1<0.17.75.65075
 Djibouti40350854.293188
 Eritrea22792714935.221  4597
 Ethiopia 375444882731515.518.55.75301.60.46473
 Kenya 179342197395117.516.55.04.02.67681
 Madagascar 88411124166516.55.439382
 Malawi6883882130716.517.56.14903.72.59587
 Mauritius63154981.949697
 Mozambique107581262203215.518.55.68107372
 Reunion40134652.497
 Rwanda4651546110020.518.55.9787599
 Somalia42154937655.7739
 Tanzania143481936289616.518.56.876064
 Uganda196012421393216.517.55.74809783
 Zambia5893738118216.516.55.95605.71.89380
 Zimbabwe6426865156818.53.968010.85.28262
Southern Africa
 Botswana9241082113.31708697
 Lesotho10581282384.11507783
 Namibia102112721218.518.54.211017.85.87986
 South Africa244132481490717.52.9320017.39.68897
 Swaziland578791324.41002.01.97795
 Sub-Saharan Africa46181055320 (12.0%)h94121 (20.4%)h 12000

The role of HIV infection in the development of cervical cancer

With the diverse HIV epidemic in sub-Saharan Africa, we must consider how it may affect HPV-related cervical disease and other genital neoplasms. This may greatly vary by region, since the estimated number of women living with HIV ranges from <1000 cases in Comoros to 3.2 million in South Africa (Table 2) (UNAIDS 2008).

Epidemiological studies, mostly conducted in developed countries, have shown that HIV-infected women are at higher risk of being infected with HR HPV (Sun et al. 1997; Ahdieh et al. 2000; Jamieson et al. 2002), and are at a higher risk for persistence and associated cervical disease progression than HIV-uninfected women (Mayaud et al. 2001; Didelot-Rousseau et al. 2006; Moscicki et al. 2006; Palefsky et al. 2006; Blossom et al. 2007). This suggests that CD4+ T-lymphocyte counts may play a role in the natural history of HPV infection. However, HPV persistence and SIL have been observed in young HIV-positive women with normal CD4+ counts, which indicates that immune factors other than CD4+ counts may play a role in disease progression. Clinical studies have shown conflicting results with some favouring HPV clearance and others persistence (Moscicki et al. 2006). In the African setting, high prevalence of sexually transmitted infections and other communicable diseases may influence immune status in cervical carcinogenesis, but few or no data are available to clarify these associations.

Both HIV and HPV infections have viral factors, and thrive on host factors that impair the immune system, which can cause considerable comorbidity and mortality. HIV-related immune alteration appears to increase the risk of cervical disease progression (Strickler et al. 2003; Hawes et al. 2006). However, after antiretroviral therapy (ART), the immune system is able to recover and better able to control HIV-related opportunistic infections and cancers, such as human herpes virus-8 (HHV-8) and associated Kaposi′s sarcoma (Ahdieh-Grant et al. 2004; Hessol et al. 2004; Clifford et al. 2006). It has been hypothesized that ART has the potential to restore the immune response against HPV, reduce HPV persistence, and should therefore be able to reduce the occurrence of pre-cancerous lesions and favour regression. Some studies have shown a beneficial effect of ART in European (Heard et al. 1998) and US cohorts (Ahdieh-Grant et al. 2004). However, other studies have not found the same benefits of ART on regression of lesions (Orlando et al. 1999; Lillo et al. 2001; Moore et al. 2002; Schuman et al. 2003; Clifford et al. 2005). In a pooled analysis of data from six European centres where women had access to ART and one community-based South African cohort of HIV-positive women with no access to ART, similar hazard ratios for developing high-grade cervical disease were observed in the European centres and in South Africa (Kitchener et al. 2007). Among these conflicting data, a consensus on the effects of ART, and on how to best manage and prevent cervical cancer in HIV-positive women, remains to be found.

The rapid extension of access to antiretroviral programmes in sub-Saharan Africa, with its more intensive and organized follow-up offers the opportunity to assess the effects of ART on cervical disease. To inform possible screening strategies, HPV infection should be evaluated at various stages of HIV disease, such as in women who do not yet require ART, in women initiating ART, or in women with long-term use of ART. This will not only help shed light on the effects of different levels of HIV immunosuppression on the temporal development of pre-neoplastic changes, but it will also help clarify the potential sustainable gains in preventing cervical cancer with antiretroviral therapy.

HPV prevalence and genotype-distribution in HIV positive women

Few studies have reported on the prevalence of HPV among HIV-positive women in SSA. Among the available data, Figure 3 shows the five most common HR-HPV types among HIV-positive women with normal cytology and SIL from a meta-analysis (HPV Information Centre 2009) and two ICC studies in Kenya and the Zambia (Sahasrabuddhe et al. 2007; De Vuyst et al. 2008). Few studies have included ICC cases with HPV type-specific data according to HIV serostatus in the region (Table 1). One study in Kenya (n = 204) found no significant differences in HPV 16/18 prevalence distribution according to HIV serostatus (De Vuyst et al. 2008). HIV-positive women with ICC have more multiple infections than in HIV-negative women, which complicates the HPV type distribution comparison by HIV status (De Vuyst et al. 2008). About 50% of HIV-positive women with HPV16 and/or 18 ICC cases are co-infected with another HPV type, so it is unclear whether the other HR types would be responsible for invasive disease in the absence of HPV16 or 18 (De Vuyst et al. 2008). These data suggest that current HPV vaccines containing HPV16/18 have the potential to prevent perhaps fewer ICC cases among HIV-positive women. It would be important to understand the potential differences between HIV-positives and negatives with additional immune correlated data among HIV-positives, such as CD4+ count.

image

Figure 3.  The five most frequent high-risk HPV types among HIV-positive women with normal cytology, low-grade intraepithelial lesions (LSIL), high-grade intraepithelial lesions (HSIL), and invasive cervical cancer (ICC) in sub-Saharan Africa [Clifford et al., 2006; Sahasrabuddhe et al., 2007de Vuyst et al., 2008).

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Cervical cancer screening

Cytology screening programmes have been successful in curbing the incidence of ICC in developed countries (Sankaranarayanan et al. 2001), but they have largely failed in most developing countries due to competing health priorities and lack of resources including health infrastructure (trained cytotechnologists, laboratories and services for diagnosis and treatment), human and financial resources (Denny et al. 2006). According to population-based surveys conducted by WHO in 2001 and 2002, cervical screening coverage was at best 20.2% of urban and 14.0% of rural areas in the Congo, and at worst, 1.6% of urban and 0.4% of rural areas in Ethiopia (WHO 2002) (Table 2). South Africa is the only country in sub-Saharan Africa to have established a national cytology-based cervical screening programme in 2001. However, coverage remains poor and the impact on ICC rates is unknown (Kawonga & Fonn 2008).

VIA (visual inspection with acetic acid) or VILI (visual inspection with Lugol’s iodine) are less laboratory dependent strategies and have been advocated as screening alternatives in developing countries (Denny et al. 2006). In various evaluation studies, VIA has shown to have a sensitivity and specificity of 60–94% and 74–94%, respectively, to detect high-grade lesions in Africa; and VILI has shown to have a sensitivity and specificity of 90–97% and 73–91%, respectively (Sankaranarayanan et al. 2001). The specificity of VIA is however lower among HIV-positive women, which may be attributed to high rates of coinfections in the lower genetal tract (Denny et al. 2002). A number of completed and ongoing screening activities using VIA and VILI have been evaluated as different strategies in the region (Table 3) (IARC Screening Group 2009). Among 20 countries reporting screening activities, 11 countries have ongoing programmes. Of the 49 projects that have been initiated, 27 projects are ongoing, but only six projects were funded by the Ministry of Health in the country. Most screening programmes in sub-Saharan Africa have been initiated as research or pilot projects (88%), and only a limited number of countries (n = 6) have received financial support or have the local political support to scale up national screening programmes.

Table 3.   Completed or ongoing cervical screening activities in sub-Saharan Africa
CountryDateProject/Program TitleType of ProgrammeSource of FundingCurrent Status
  1. Data aggregated from [IARC Screening Group, 2009]. Accessed 23 April 2009. *VIA, visual inspection with acetic acid; VILI, visual inspection with Lugol’s iodine

Angola2002–2004Comparative evaluation of early detection of cervical cancer precursors by VIA and with VILI and establishment of a cervical cancer prevention training centreResearchIARC (Screening services continue with local funds to date in 2008)Active
Benin2008–2009Screening of cervical intra epithelial lesions in women living with HIV; Case-control study about pap-smear done in Parakou hospital between 2008 and 2009. Research associated with HIV projectUnknownCompleted
Botswana2005–2009Botswana National Cervical Cytology (Cancer) Screening ProgrammeMoHNoneActive
Burkina Faso2000–2002Comparative evaluation of early detection of cervical cancer precursors by VIA and VILIResearchIARCCompleted
 2003–2004Human papillomavirus genotype distribution and cervical squamous intraepithelial lesions among high-risk women with and without HIV-1 infectionResearchMontpellier University HospitalCompleted
 2007–2012Prevention of cervical cancer in Burkina Faso (Ouagadougou and Bobo Dioulasso)Pilot projectSociete des obstetriciens et gyncecologues du Canada (SOGC); Agence canadienne de developpement international (ACDI)Approved/ Not yet active
Congo, Republic of2000–2004Comparative evaluation of early detection of cervical cancer precursors by VIA and VILIResearchIARCCompleted
 2004–2008Screening and treatment of cervical precancerous lesionsResearchLocal fundsActive
Ethiopia2006–2008Comparison of PAP smear, VI A/VTLI for cervical cancer screeningMoHWHO, UNFPA, UNICEFActive
Ghana2001–2003Safety, Acceptability, and Feasibility of a Single Visit Approach to Cervical Cancer Prevention – A Demonstration ProjectPilot projectJHPIEGO; Bill and Melinda Gates FoundationCompleted
Guinea2000–2003Comparative evaluation of early detection of cervical cancer precursors by VIA and VILIResearchIARC (Screening services continue with local funds to date in 2008)Completed
 2003–2004Organized cervical cancer screening program using visual inspection methods in the region of KhoriraDemonstration projectIARC (Screening services continue with local funds to date in 2008)Completed
 2004–2005Organized cervical cancer screening program using VIA/VILI in ConakryDemonstration projectIARC (Screening services continue with local funds to date in 2008)Active
Kenya2000–2004Western Kenya Cervical Cancer Prevention Project (WKCCPP) UnknownPATHCompleted
Madagascar2006–2008Prevention of cervical cancer through screening using VIA and treatment with cryotherapy – A demonstration project in MadagascarPilot projectWHO (Headquarters)Active
Mali2001–2003Comparative evaluation of early detection of cervical cancer precursors by VIA and VILIResearchIARCCompleted
 2004–2007Organized cervical cancer screening program using VIA/VILI in the region of BamakoDemonstration projectIARCCompleted
Malawi2000–2002Cervical Cancer Screening & Early Treatment (CCSET) Pilot ProjectPilot ProjectDFID (Project Hope) Bill and Melinda Gates Foundation (JHPIEGO)Completed
 2004–2007Cervical cancer prevention programme (CECAP) MoHUSAID (2004–2005), Bill andCompleted
      
 2006–2008Prevention of cervical cancer through screening using VIA and treatment with cryotherapy in LilongwePilot projectMelinda Gates (2005–2006), USAID (2007) WHO (Headquarters) Active
Niger2000–2004Comparative evaluation of early detection of cervical cancer precursors by VIA and VILIResearchIARCCompleted
 2004–2008Outreach clinics/campaignsOutreachSEM le president de laActive
    clinics/campaigns republique (programme special)/ UNFPA 
Nigeria2006–2008Prevention of cervical cancer through screening using VIA and treatment with cryotherapy – A demonstration project in SgamuPilot projectWHO (Headquarters)Active
 2006–2008Lagos cervical cancer screening project Institute for Women’s healthActive
 2006–2010Operation “Stop cervical cancer in Nigeria”ResearchNCI/NIH/FED-EX/T. BOONE PICKINS/EXXONMOBIL FOUNDATION/Active
 2008–2009Edo State Cervical Cancer Control programmeMoHEdo State GovernmentActive
South Africa1996–1999Khayelitsha cervical cancer screening project (KCCSP)  Engender Health / University ofCompleted
    Cape Town 
 2000–2003Randomised control trial of screening and treating women based on D VI and HPV testing (KCCSP)  University of Cape Town / Columbia University (NewCompleted
    York) / Engender Health 
 2003–2009The Cervical Health Implementation Project (CHIP)  University of Cape Town / Columbia University (New York) / Engender HealthActive
 2007–2009Increasing Access to Cervical Cancer Prevention in South Africa’s North West ProvincePilot ProjectJHPIEGO / Northwest Province (NWP) health departmentActive
 2007–2010Application and cost-effectiveness of new technologies such as liquid based cytology and computer-assisted cervical screening to women at high risk for the development of cervical cancer. Cervical cancer prevention training actionsNational Health Laboratory Service, JohannesburgActive
Senegal2009–2010Cervical cancer prevention by single-visit approach in DakarPilot projectSeeking FundsNot yet active
Tanzania2002–2008Comparative evaluation of VIA and VILI to test cervical cancer in the early detection and prevention of cervical neoplasia and establishment of a cervical cancer prevention training centre in TanzaniaResearchIARC / Ocean Road Cancer Institute (ORCI) / International Network of Cancer Treatment and Research (INCTR) (Screening services continue with local funds to date in 2008)Active
 2006–2008Prevention of cervical cancer through screening using VIA and treatment with cryotherapy – A demonstration project in Moshi, Kilimanjaro regionPilot ProjectWHO (Headquarters)Active
 2006–2008Prevention of cervical cancer through screening using VIA and treatment with cryotherapy – A demonstration project in PeramihoPilot ProjectWHO (Headquarters)Active
 2006–2008Outreach clinics/campaigns in 5 regions (Mwanga, Morogoro, Muheza, Mwanza and Bagamoyo) Outreach clinics/campaignsOcean RoadActive
Uganda2006–2008Prevention of cervical cancer through screening using VIA and treatment withPilot projectWHO (Headquarters)Active
  Cryotherapy – A demonstration project in Masaka   
 2006–2009UCL – Uganda Women’s Health Initiative (Kampala project)  Institute for Women’s Health, University College, LondonActive
 2007Kisoro district hospital Albert Einstein UniversityActive
 2007–2010Nsambya Hospital (USA) MRC/UVRI EntebbeActive
 2008 2008Project Mildmay Center Nsyamba hospital/Gulu hospital CDC/PEPFA (USA) MRCActive
 2008–2011VIA (Mbarara Regional referral hospital)Cervical cancer prevention training actionsPATHActive
 2008–2012Kisenyi/Mulago Canadian groupActive
 2008–2012Mulago Hospital – Obstetrics & Gynecological Department Ministry of Health and MakerereActive
 2008–2012START-UP Project: Uganda (Mulago hospital) MoHPATHActive
Zambia2006–2008Prevention of cervical cancer through screening using VIA and treatment with cryotherapy in LusakaDemonstration projectWHO (Headquarters)Active
 2006–2008CIDRZ project at University Teaching Hospital, LusakaMoHCIDRZActive
Zimbabwe1996–1997VIA as a cervical cancer test: accuracy validated using latent class analysis. ResearchUSAID / JHPIEGOCompleted

While visual inspection methods appear effective for primary screening, they are still prone to subjectivity, requiring good provider training and sustained quality assurance in order to achieve substantial gains in prevention of cervical cancer in routine settings (Sankaranarayanan et al. 2007; Muwonge et al. 2009).

A more objective and reproducible screening test is testing for HPV DNA that has shown to be more sensitive than cervical cytology in detecting high-grade lesions (ACOG Practice Bulletin 2005; Dillner et al. 2008). A screening trial using HPV testing for 6553 unscreened women (35–65 years) in South Africa showed an 80% reduction of CIN2+ by 36 months of follow-up among HIV-infected women, which was similar to the reduction among HIV-uninfected women (Kuhn et al. 2009). In addition, a cluster-randomized trial of about 132 000 women (30–59 years) in rural India showed that a single round of HPV DNA testing significantly reduced the rate of advanced stages of cervical cancers and associated deaths compared to VIA, cytology and no screening after 8 years of follow-up (Sankaranarayanan et al. 2009). These studies suggest that HPV testing is an appropriate primary screening approach in low-resource settings to reduce cases of high-grade lesions, advanced stages of ICC and mortality in HIV-infected and uninfected women.

Rapid HPV DNA testing

The limitations of HPV DNA testing include the cost (i.e. US$20–30 per test), infrastructure, and time needed to obtain a result. However CareHPV (Qiagen Gaithersburg Inc., MD, USA) has been developed as a simple, rapid and operational HPV test for low-resource settings that can produce results within 3 h (Qiao et al. 2008). The compact, portable and battery-operated technology has stable conditions, and the test can be conducted by workers with minimal training. Data from China showed that, compared to VIA, CareHPV has a higher sensitivity (90%vs. 41%) and a reasonably comparable specificity (84%vs. 94%) to detect high-grade lesions. Moreover, a modelling analysis found that CareHPV has the potential to reduce the incidence of cervical cancer by 56% in China if given just three times over a woman′s lifetime and effective treatment is available (Levin et al. 2008), suggesting its potential impact in reducing the burden of ICC in comparable settings. Regulatory approval is anticipated in developing countries in the near future, and this test will be provided at a low-cost. CareHPV represents a promising alternative screening test, however, its performance and diagnostic value to detect pre-cancerous lesions need to be evaluated in African settings.

Effective cervical screening programmes

Apart from affordable, acceptable and effective screening tools, the performance of a screening programme is dependent on multiple factors, such as information and education for women and communities in order to obtain their participation into screening programmes. After screening, acceptable and accessible referral services for diagnosis and effective treatment, and good follow-up are required for a successful programme (Gravitt et al. 2008). At present, this may involve a three-visit strategy with initial screening evaluation at the first visit, performing colposcopy for those who screen positive at the second visit, and treating biopsy-confirmed cervical lesions at the third visit. In order to avoid loss-to-follow-up, a ‘screen-and-treat’ approach should be considered, where referral/treatment is offered immediately to screen-positives cases with a reduced number of clinical visits (Blumenthal et al. 2007). A cost-effective model for five developing countries which included South Africa showed that screening with one-visit or two-visits in a lifetime using visual inspection or HPV DNA test coupled with immediate cryotherapy for screened positives for women aged 35 years or older has the potential to reduce the lifetime risk of cancer by 25–35% compared with no screening (Goldie et al. 2005). In sub-Saharan Africa, where minimal cervical screening services are available, this once in a lifetime screen-and-treat strategy may have an important impact in reducing the incidence of ICC and needs to be evaluated locally to determine whether it is logistically feasible, acceptable and safe.

Prospects of HPV vaccination: opportunities and challenges

Prophylactic HPV vaccines give new promises for a primary prevention strategy for HPV infection and cervical cancer. The vaccines have shown high safety, efficacy and immunogenicity for both the quadrivalent HPV 16/18/6/11 vaccine (Gardasil®, Merck & Co., Inc.) and the bivalent HPV 16/18 vaccine (Cervarix™, GlaxoSmithKline Biologicals) (Schiller et al. 2008). A number of countries in sub-Saharan Africa have licensed the HPV vaccines (Table 4). However, implementation plans are lagging and will depend largely on the affordability of the vaccines, and a clear cost-benefit ratio. We further discuss some of the challenges that will be met prior to introduction of the HPV vaccines in sub-Saharan Africa.

Table 4.   HPV vaccines licensure in sub-Saharan Africa, as of March 2009
Quadrivalent HPV 6/11/16/18 Vaccine (Gardasil® Merck, SA) (18)Bivalent HPV 16/18 Vaccine (Cervarix®, GSK) (10)
  1. *Source: HPV Information Centre, 2009.

BotswanaCongo
Burkina FasoCote d’lvoire
CameroonGabon
Central African RepublicGhana
ChadKenya
CongoNamibia
Cote d’lvoireNigeria
Democratic Republic of CongoSenegal
Equatorial GuineaSouth Africa
EthiopiaUganda
Gabon 
Kenya 
Malawi 
Mauritania 
Mauritius 
South Africa 
Togo 
Uganda 

Vaccine efficacy, safety and immunization schedules

HPV vaccines have shown 95% efficacy in preventing vaccine HPV types and related precancerous lesions for up to 7 years in large international cohorts of women, although noticeably, excluding Africa (Schiller et al. 2008). However, safety and immunogenicity bridging studies are currently being conducted in young HIV-negative women in Senegal and Tanzania (ClinicalTrial.gov NCT00481767). In addition, these studies will investigate the effect of the vaccines in populations whose immunological system may be challenged by multiple co-infections such as malaria and helminths, which may possibly modify immune response (Lehtinen et al. 2006). Until recently, there were no data on HPV vaccination among those infected with HIV. Clinical trials are underway in HIV positive women in South Africa (ClinicalTrial.gov NCT00586339) and results are eagerly awaited from this endemic region. In addition, initial results from a quadrivalent vaccine trial of 126 perinatally infected HIV-infected children (7–12 years) in North America have shown that the vaccine is generally safe and nearly 100% seroconverted although antibody titres for HPV 16 and 18 were lower than in healthy children (Moscicki et al. 2009).

In order to evaluate the potential reductions in costs, a multi-centre study involving about 16 000 girls aged 10–18 years to evaluate the effectiveness and safety of two- vs. three-doses HPV vaccine in preventing cervical cancer is underway (Sankaranarayanan et al. 2008) and trials of giving HPV vaccines to babies as part of the standard infant immunization schedule are being discussed (Garland et al. 2008). Results from these studies may facilitate a wider rollout of HPV vaccine in sub-Saharan Africa.

Vaccine delivery challenges

The adoption of the vaccines into a national immunization programme will only be realized when the HPV vaccines drop in price and they become part of the essential WHO Expanded Program of Immunization (EPI) vaccines (Kane et al. 2006). EPI programmes have been successful in improving access and delivery of vaccines to children and achieving high coverage worldwide. In 2007, vaccination coverage of the target population for DTP for the third dose was as low as 33% in Equatorial Guinea to 99% in Burkina Faso (Table 2). Infrastructure of trained staff, cold chain and logistics, clinics and outreach services and information systems are already established to deliver these infant vaccines. However, even if the vaccine is incorporated onto the EPI list, there still remains the challenge of delivering an ‘adolescent’ vaccine since no programme exists targeting this population. In order to be highly efficacious, vaccines should be delivered prior to sexual initiation when risk of exposure to HPV increases.

Current vaccines target pre-adolescent and young women, and developing a school-based programme with this target population will be challenging, as few continue their secondary school education beyond primary school. Net school enrolment in primary school ranges from as low as 31% in Dijibouti to 97% in Tanzania (Table 2). Even if the vaccine were to be considered at the primary school level, those who need the vaccine the most may be less likely to attend school (Kane et al. 2006) as sexual activity among adolescents in out-of-school females is common (Brown et al. 2001). However, measles campaigns in Africa using schools as vaccination sites to bring non-school attendees to the vaccination site has been reported and is a strategy that could be explored for HPV vaccines (Kane et al. 2006).

Local communities will need to first identify factors that influence vaccine acceptability and uptake among target populations and healthcare providers, and then decide the most appropriate way for vaccine deployment. For example, PATH, an international NGO which focuses on reproductive health research, has conducted formative research in Uganda to evaluate the psychosocial aspects of vaccine acceptability and to understand health systems that are required to guide effective vaccine delivery strategies, communication and advocacy (PATH 2009). The results from this research are being used to explore two possible vaccination implementation strategies: (i) ‘Child Days Plus’ is a semi-annual event that aims to vaccinate children as part of an integrated health service programme; and (ii) school-based vaccination programme. Findings from the demonstration project are expected in 2010.

Vaccine costs and cost-effectiveness

At US$360 for the three-dose HPV vaccine, it is the most expensive vaccine in history. This is difficult to accept as 80% of cases of cervical cancer occur in developing countries (Parkin & Bray 2006), where health budgets are very limited. In order to overcome cost barriers, work is being done to facilitate innovative financial mechanisms to accelerate the introduction of vaccines, such as advanced market commitments, which provides an assured price subsidy for developing country purchase of a future vaccine meeting predefined standards and will provide industry with assurances of earning a reasonable return on their investment. Another solution would be public-private partnerships, which will allow both the public and private sectors to share the risks and costs of developing, scaling-up and introducing priority vaccines (Batson et al. 2006). In 2008, the GAVI Alliance a public-private organization dedicated to increasing children’s access to vaccines in developing countries has included the HPV vaccine amongst its priority of new vaccines to be considered for introduction. If subsidized by the GAVI Alliance, the vaccine could reach over 80% of the countries in sub-Saharan Africa.

An economic analysis evaluating the impact of vaccination in GAVI eligible countries showed that with 70% coverage of pre-adolescents, HPV vaccines have the potential to reduce the lifetime risk of cervical cancer by 31–60% in the region (Goldie et al. 2008). Hypothetically, if the cost to vaccinate a girl was US$2 per dose, the vaccine would be cost-effective compared to no vaccination in all sub-Saharan African countries and it would be cost-saving and less than international dollars I$100 per disability-adjusted years of life (DALYs) averted in a few countries, e.g. Comoros, Guinea, Lesotho, Zimbabwe, Rwanda, Eritrea, Uganda and Djibouti. However, each country will need to conduct its own economic analyses to evaluate their budgets for introduction of the HPV vaccine among other new childhood vaccines (i.e. rotavirus, pneumococccal, meningococcal meningitis) being considered. It is still unknown whether one lifetime cervical screening and treatment may be more cost-effective than HPV vaccination in preventing cervical cancer deaths in each of these sub-Saharan African countries. Further evaluation of a number of strategies considering vaccination and screening only or in combination will also be needed to inform the most appropriate cost-effectiveness prevention strategy.

Summary of gaps in knowledge

In order to strengthen the efforts of cervical cancer prevention in sub-Saharan Africa, we highlight the following gaps in knowledge:

Epidemiology:

  •  Better cancer registry data to assess the burden of cervical cancer;
  •  Basic epidemiological data of HPV prevalence and genotype-distribution among women in the general population according to HIV serostatus to evaluate the potential impact of HPV vaccines and cervical cancer screening strategies;
  •  Longitudinal data on HIV infected women to evaluate the impact of ART on HPV infection and cervical disease;
  •  Long-term impact of HPV vaccines in preventing actual cases of cervical cancer.

Cervical screening:

  •  Evaluation of VIA, VILI in conjunction with HPV testing (e.g. with CareHPV) as screening tools in a ‘screen-and-treat’ approach;
  •  Evaluation of screening strategies in HIV-positive populations, including those taking ART.

HPV vaccine delivery:

  •  Vaccine trials in infants to evaluate the potential inclusion as part of an EPI standard immunization schedule;
  •  Vaccine deployment considerations: (i) community acceptability; (ii) health system capacity and channels of vaccine delivery; (iii) vaccination strategies, including appropriate age and sex, and catch-up strategies, (iv) health economics and impact modelling;
  •  Cost-effectiveness studies of vaccine and/or cervical screening strategies;
  •  Comparative analyses of cervical screening and/or vaccination strategies on disease impact.

Conclusions

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Conclusions
  7. References

The burden of cervical cancer is potentially large in sub-Saharan Africa and there is an urgency to make it a public health priority. Sub-Saharan Africa is vastly heterogeneous and each country will need to decide on a realistically feasible cervical cancer prevention and control strategy. Existing data should be used to initiate plans and projects to better understand the current situation and programmes will need to take into consideration the impact of HIV co-infection to adequately address both health needs. The availability of low-cost cervical screening technologies of HPV testing and visual inspection methods and HPV vaccines represent tools that provide realistic opportunities for cervical cancer prevention in sub-Saharan Africa. In order to successfully introduce, implement and sustain a prevention programme, good data from across multi-disciplines dedicated to the prevention of cervical cancer are needed.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Conclusions
  7. References
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