HPV AND CERVICAL CANCER IN SUB-SAHARAN AFRICA

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'ICC incidence in SSA is one of the highest in the world with an age-standardized incidence rate of 31 per 100,000 women.'

Of the 46 countries in WHO's African region, only Rwanda is introducing HPV vaccination into its national vaccination programme. One down, 45 to go.

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Bob Davis

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http://onlinelibrary.wiley.com/doi/10.1111/j.1365-3156.2009.02372.x/full

Epidemiology and prevention of human papillomavirus and cervical cancer in sub-Saharan Africa: a comprehensive review

Karly S. Louie1,2,

Silvia De Sanjose2,3,

Philippe Mayaud1

Article first published online: 14 SEP 2009

Tropical Medicine & International Health

Volume 14, Issue 10, pages 1287–1302, October 2009

How to Cite

Louie, K. S., De Sanjose, S. and Mayaud, P. (2009), Epidemiology and prevention of human papillomavirus and cervical cancer in sub-Saharan Africa: a comprehensive review. Tropical Medicine & International Health, 14: 1287–1302. doi: 10.1111/j.1365-3156.2009.02372.x

Author Information

1  Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK

2  Unit of Infections and Cancer, Cancer Epidemiology Research Program, Institut Catalá d’Oncologia, Barcelona, Spain

3 CIBER en Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain

*Correspondence: Corresponding Author Karly S. Louie, Department of Infectious & Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK. Tel.: 44 20 7927 2291; Fax: 44 20 7637 4314; E-mail: Karly.Louie@lshtm.ac.uk

Publication History

Issue published online: 14 SEP 2009

Article first published online: 14 SEP 2009

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

Top of page

Abstract

Introduction

Methods

Results

Conclusions

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

Top of page

Abstract

Introduction

Methods

Results

Conclusions

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

Top of page

Abstract

Introduction

Methods

Results

Conclusions

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).

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

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

Country

No. of women with ICC tested

HPV16/18 Prevalence, % (95% CI*)

a Estimates from HPV Information Centre, 2009.

b Estimates from De Vuyst et al., 2008.

c Estimates from Sahasrabuddhe et al., 2007.

*CI, confidence interval.

HIV-negative womena

 Benin

6

66.7 (28.9–100.0)

 Guinea

18

44.4 (21.5–67.4)

 Ethiopia

163

90.2 (85.6–94.8)

 Kenya

261

60.9 (55.0–66-8)

 Mozambique

302

79.1 (74.6–83.7)

 Mali

123

54.5 (45.7–63.3)

 Senegal

71

43.7 (32.1–55.2)

 South Africa

307

62.9 (57.5–68.3)

 Tanzania

102

72.6 (63.9–81.2)

 Uganda

154

74.0 (67.1–81.0)

 Zimbabwe

98

79.6 (71.6–87.6)

 Total

1605

69.2 (66.9–71.4)

HIV-positive women

 Kenyab

51

68.6 (55.9–81.4)

 Zambiac

28

53.6 (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).

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].

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)a

Women Aged 10-14 (thousands)a

Women Aged 15-24 (thousands)a

Age at first sexual intercourseb

Total Fertilityb

Estimated number of women 15+ years living with HIV (thousands)d

Cervical Screening Coverage, %c,e

Net primary school enrolment ratio (%)c, f

Vaccine coverage (%) 2007 of DTP (3rd dose)g

 

Female

Male

Urban

Rural

 

aPopulation in 2005. World population prospects: the 2008 revision. New York, Population Division, Department ot Economic and Social Attairs, United Nations Secretariat, 2009.

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

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

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

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

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.

hPercentage of Total population in sub-Saharan Africa.

 

Central Africa

 

 Angola

8426

1088

1670

6.9

110

83

 

 Cameroon

8928

1107

1862

15.5

18.8

5.2

300

82

 

 Central African

 

 

 

15.5

17.5

 

91

 

 

 

 Republic

2089

248

416

 

 

5.2

 

 

 

54

 

 Chad

5045

629

982

15.5

18.5

6.6

110

9.5

4.0

49

20

 

 Congo

1713

210

356

4.7

43

20.2

14.0

58

80

 

 DRC Congo

29828

3853

5786

7.3

87

 

 Equator. Guinea

307

38

56

5.6

6

83

33

 

 Gabon

687

86

138

15.5

17.5

4.3

27

88

38

 

 Sao Tome and

 

 

 

 

 

 

 

 Principe

77

10

18

 

 

4.7

 

 

 

95

97

 

West Africa

 

 Benin

3912

480

346

17.5

17.5

5.8

37

69

67

 

 Burkina Faso

6896

861

636

17.5

20.5

6.2

61

7.8

5.1

39

99

 

 Cape Verde

250

32

25

4.2

89

81

 

 Cote d’lvoire

9402

1168

890

15.5

18.5

4.7

250

6.9

3.1

49

76

 

 The Gambia

770

91

65

6.0

5

72

90

 

 Ghana

10812

1292

1025

17.5

19.5

4.6

150

3.2

2.2

64

94

 

 Guinea

4565

561

406

15.5

17.5

5.6

48

63

75

 

 Guinea-Bissau

743

86

61

6.8

9

37

63

 

 Liberia

1680

205

152

5.2

19

58

88

 

 Mali

5992

758

567

15.5

19.5

6.9

56

7.6

3.4

52

68

 

 Mauritania

1474

174

139

4.6

4

4.5

1.0

79

75

 

 Niger

6548

822

571

20.5

7.1

17

36

39

 

 Nigeria

70381

8535

6632

15.5

20.5

5.7

1400

59

54

 

 Senegal

5681

730

543

15.5

20.5

5.2

38

6.8

6.9

68

94

 

 Sierra Leone

2626

303

248

6.6

30

64

 

 Togo

3028

371

292

15.5

5.4

69

72

88

 

East Africa

 

 Burundi

3776

487

857

5.6

53

55

74

 

 Comoros

307

34

67

18.5

5.1

<0.1

7.7

5.6

50

75

 

 Djibouti

403

50

85

4.2

9

31

88

 

 Eritrea

2279

271

493

5.2

21

 

 

45

97

 

 Ethiopia

37544

4882

7315

15.5

18.5

5.7

530

1.6

0.4

64

73

 

 Kenya

17934

2197

3951

17.5

16.5

5.0

4.0

2.6

76

81

 

 Madagascar

8841

1124

1665

16.5

5.4

3

93

82

 

 Malawi

6883

882

1307

16.5

17.5

6.1

490

3.7

2.5

95

87

 

 Mauritius

631

54

98

1.9

4

96

97

 

 Mozambique

10758

1262

2032

15.5

18.5

5.6

810

73

72

 

 Reunion

401

34

65

2.4

97

 

 Rwanda

4651

546

1100

20.5

18.5

5.9

78

75

99

 

 Somalia

4215

493

765

5.7

7

39

 

 Tanzania

14348

1936

2896

16.5

18.5

6.8

760

64

 

 Uganda

19601

2421

3932

16.5

17.5

5.7

480

97

83

 

 Zambia

5893

738

1182

16.5

16.5

5.9

560

5.7

1.8

93

80

 

 Zimbabwe

6426

865

1568

18.5

3.9

680

10.8

5.2

82

62

 

Southern Africa

 

 Botswana

924

108

211

3.3

170

86

97

 

 Lesotho

1058

128

238

4.1

150

77

83

 

 Namibia

1021

127

212

18.5

18.5

4.2

110

17.8

5.8

79

86

 

 South Africa

24413

2481

4907

17.5

2.9

3200

17.3

9.6

88

97

 

 Swaziland

578

79

132

4.4

100

2.0

1.9

77

95

 

 Sub-Saharan Africa

461810

55320 (12.0%)h

94121 (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 Kaposis 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.

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).

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

Country

Date

Project/Program Title

Type of Programme

Source of Funding

Current Status

Data aggregated from [IARC Screening Group, 2009]. Accessed 23 April 2009. *VIA, visual inspection with acetic acid; VILI, visual inspection with Lugol’s iodine

Angola

2002–2004

Comparative evaluation of early detection of cervical cancer precursors by VIA and with VILI and establishment of a cervical cancer prevention training centre

Research

IARC (Screening services continue with local funds to date in 2008)

Active

Benin

2008–2009

Screening 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 project

Unknown

Completed

Botswana

2005–2009

Botswana National Cervical Cytology (Cancer) Screening Programme

MoH

None

Active

Burkina Faso

2000–2002

Comparative evaluation of early detection of cervical cancer precursors by VIA and VILI

Research

IARC

Completed

 

2003–2004

Human papillomavirus genotype distribution and cervical squamous intraepithelial lesions among high-risk women with and without HIV-1 infection

Research

Montpellier University Hospital

Completed

 

2007–2012

Prevention of cervical cancer in Burkina Faso (Ouagadougou and Bobo Dioulasso)

Pilot project

Societe des obstetriciens et gyncecologues du Canada (SOGC); Agence canadienne de developpement international (ACDI)

Approved/ Not yet active

Congo, Republic of

2000–2004

Comparative evaluation of early detection of cervical cancer precursors by VIA and VILI

Research

IARC

Completed

 

2004–2008

Screening and treatment of cervical precancerous lesions

Research

Local funds

Active

Ethiopia

2006–2008

Comparison of PAP smear, VI A/VTLI for cervical cancer screening

MoH

WHO, UNFPA, UNICEF

Active

Ghana

2001–2003

Safety, Acceptability, and Feasibility of a Single Visit Approach to Cervical Cancer Prevention – A Demonstration Project

Pilot project

JHPIEGO; Bill and Melinda Gates Foundation

Completed

Guinea

2000–2003

Comparative evaluation of early detection of cervical cancer precursors by VIA and VILI

Research

IARC (Screening services continue with local funds to date in 2008)

Completed

 

2003–2004

Organized cervical cancer screening program using visual inspection methods in the region of Khorira

Demonstration project

IARC (Screening services continue with local funds to date in 2008)

Completed

 

2004–2005

Organized cervical cancer screening program using VIA/VILI in Conakry

Demonstration project

IARC (Screening services continue with local funds to date in 2008)

Active

Kenya

2000–2004

Western Kenya Cervical Cancer Prevention Project (WKCCPP)

Unknown

PATH

Completed

Madagascar

2006–2008

Prevention of cervical cancer through screening using VIA and treatment with cryotherapy – A demonstration project in Madagascar

Pilot project

WHO (Headquarters)

Active

Mali

2001–2003

Comparative evaluation of early detection of cervical cancer precursors by VIA and VILI

Research

IARC

Completed

 

2004–2007

Organized cervical cancer screening program using VIA/VILI in the region of Bamako

Demonstration project

IARC

Completed

Malawi

2000–2002

Cervical Cancer Screening & Early Treatment (CCSET) Pilot Project

Pilot Project

DFID (Project Hope) Bill and Melinda Gates Foundation (JHPIEGO)

Completed

 

2004–2007

Cervical cancer prevention programme (CECAP)

MoH

USAID (2004–2005), Bill and

Completed

 

 

 

 

 

 

 

2006–2008

Prevention of cervical cancer through screening using VIA and treatment with cryotherapy in Lilongwe

Pilot project

Melinda Gates (2005–2006), USAID (2007) WHO (Headquarters)

Active

Niger

2000–2004

Comparative evaluation of early detection of cervical cancer precursors by VIA and VILI

Research

IARC

Completed

 

2004–2008

Outreach clinics/campaigns

Outreach

SEM le president de la

Active

 

 

 

 clinics/campaigns

 republique (programme special)/ UNFPA

 

Nigeria

2006–2008

Prevention of cervical cancer through screening using VIA and treatment with cryotherapy – A demonstration project in Sgamu

Pilot project

WHO (Headquarters)

Active

 

2006–2008

Lagos cervical cancer screening project

 

Institute for Women’s health

Active

 

2006–2010

Operation “Stop cervical cancer in Nigeria”

Research

NCI/NIH/FED-EX/T. BOONE PICKINS/EXXONMOBIL FOUNDATION/

Active

 

2008–2009

Edo State Cervical Cancer Control programme

MoH

Edo State Government

Active

South Africa

1996–1999

Khayelitsha cervical cancer screening project (KCCSP)

 

Engender Health / University of

Completed

 

 

 

 

Cape Town

 

 

2000–2003

Randomised control trial of screening and treating women based on D VI and HPV testing (KCCSP)

 

University of Cape Town / Columbia University (New

Completed

 

 

 

 

York) / Engender Health

 

 

2003–2009

The Cervical Health Implementation Project (CHIP)

 

University of Cape Town / Columbia University (New York) / Engender Health

Active

 

2007–2009

Increasing Access to Cervical Cancer Prevention in South Africa’s North West Province

Pilot Project

JHPIEGO / Northwest Province (NWP) health department

Active

 

2007–2010

Application 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 actions

National Health Laboratory Service, Johannesburg

Active

Senegal

2009–2010

Cervical cancer prevention by single-visit approach in Dakar

Pilot project

Seeking Funds

Not yet active

Tanzania

2002–2008

Comparative 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 Tanzania

Research

IARC / Ocean Road Cancer Institute (ORCI) / International Network of Cancer Treatment and Research (INCTR) (Screening services continue with local funds to date in 2008)

Active

 

2006–2008

Prevention of cervical cancer through screening using VIA and treatment with cryotherapy – A demonstration project in Moshi, Kilimanjaro region

Pilot Project

WHO (Headquarters)

Active

 

2006–2008

Prevention of cervical cancer through screening using VIA and treatment with cryotherapy – A demonstration project in Peramiho

Pilot Project

WHO (Headquarters)

Active

 

2006–2008

Outreach clinics/campaigns in 5 regions (Mwanga, Morogoro, Muheza, Mwanza and Bagamoyo)

Outreach clinics/campaigns

Ocean Road

Active

Uganda

2006–2008

Prevention of cervical cancer through screening using VIA and treatment with

Pilot project

WHO (Headquarters)

Active

 

 

Cryotherapy – A demonstration project in Masaka

 

 

 

 

2006–2009

UCL – Uganda Women’s Health Initiative (Kampala project)

 

Institute for Women’s Health, University College, London

Active

 

2007

Kisoro district hospital

 

Albert Einstein University

Active

 

2007–2010

Nsambya Hospital

 

(USA) MRC/UVRI Entebbe

Active

 

2008 2008

Project Mildmay Center Nsyamba hospital/Gulu hospital

 

CDC/PEPFA (USA) MRC

Active

 

2008–2011

VIA (Mbarara Regional referral hospital)

Cervical cancer prevention training actions

PATH

Active

 

2008–2012

Kisenyi/Mulago

 

Canadian group

Active

 

2008–2012

Mulago Hospital – Obstetrics & Gynecological Department

 

Ministry of Health and Makerere

Active

 

2008–2012

START-UP Project: Uganda (Mulago hospital)

MoH

PATH

Active

Zambia

2006–2008

Prevention of cervical cancer through screening using VIA and treatment with cryotherapy in Lusaka

Demonstration project

WHO (Headquarters)

Active

 

2006–2008

CIDRZ project at University Teaching Hospital, Lusaka

MoH

CIDRZ

Active

Zimbabwe

1996–1997

VIA as a cervical cancer test: accuracy validated using latent class analysis.

Research

USAID / JHPIEGO

Completed

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 womans 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)

*Source: HPV Information Centre, 2009.

Botswana

Congo

Burkina Faso

Cote d’lvoire

Cameroon

Gabon

Central African Republic

Ghana

Chad

Kenya

Congo

Namibia

Cote d’lvoire

Nigeria

Democratic Republic of Congo

Senegal

Equatorial Guinea

South Africa

Ethiopia

Uganda

Gabon

 

Kenya

 

Malawi

 

Mauritania

 

Mauritius

 

South Africa

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