National Policy of the Department of Health for the Prevention of Cervical Cancer in South

Draft Ca Cx Policy – September 22nd, 2011

National Policy of the Department of Health for the Prevention of Cervical Cancer in South Africa

Draft One, September 22nd, 2011

Prepared by Lynette Denny, Head of Department, Obstetrics & Gynaecology, University of Cape Town/ Groote Schuur Hospital and member of Institute of Infectious Diseases and Molecular Medicine, University of Cape Town and

Professor Greta Dreyer, Professor, Gynaecology Oncology, University of Pretoria and Steve Biko Academic Memorial Hospital

(Mapula, please put in all the relevant names, Irene le Roux, Jennifer Moodley, Waasila Jassat etc)

1 Draft Ca Cx Policy – September 22nd, 2011

1.0 Introduction:

1.1.Status of cervical cancer globally and in South Africa

In a recent analysis based on the 2008 world wide estimates of cancer compiled by the International Agency for Research on Cancer (IARC, Lyon, France) (Globocan 2008) [1] http://globocan.iarc.fr/ and http://www.who.int/hpvcentre], it was estimated that globally 529 512 women were diagnosed with cervical cancer corresponding to an Age Standardised Incidence Rate (ASIR) of 15.4/100 000. The same group estimated that 274 967 women died of the disease, with an Age Standardised Mortality Rate (ASMR) of 7.8/100 000 [M Arbyn,X Castellsague, S de Sanjose, L Bruni, M Saraiya, F Bray and J Ferlay. Worldwide burden of cervical cancer in 2008. Annals of Oncology 2011, doi:1093/annonc/mdr05]. The majority of the cases diagnosed (n = 453 032; 85.5%) were found in developing countries, as were the deaths (n = 241 818; 87.9%). Globally cervical cancer was the third most common cancer ranking after breast (1.3 million cases) and colorectal cancer (0.57 million cases) and the fourth most common cause of cancer death ranking below breast, lung and colorectal cancer. There is a striking disparity in the incidence of and mortality from cervical cancer in different regions of the world. Figure one shows the annual number of deaths from cervical cancer in developed and developing regions by age group, and it is evident that the number of deaths in developing countries is nearly 10 times greater than in developed regions [data for figure taken from reference 1].

Figure One: Annual number of deaths from cervical cancer by age group in developed and developing regions [Globocan 2008 IARC, Lyon, France][1]

In Africa, which has a population of 267.9 million women aged 15 years and older at risk of developing cervical cancer, approximately 80 000 women are diagnosed with cervical cancer per

2 Draft Ca Cx Policy – September 22nd, 2011 year, and just over 60 000 women die from the disease [1], in other words nearly 80% of women diagnosed with cervical cancer die from the disease, despite cervical cancer being both preventable and curable if detected in early stages.

Cervical cancer incidence in Africa also varies considerably by region. The highest rates in Africa (ASIR > 40/100 000) are all found in Eastern, Southern or Western Africa (Figure 2) [1]. In addition, there are marked variations within regions themselves as illustrated in Figure 3 for Southern Africa [1], where the highest incidence is found in Lesotho and Swaziland, two countries that have neither screening programs nor any anti-cancer treatment facilities and who have 1 and 2 doctors per 10 000 population respectively (compared to 8/ 10 000 in South Africa and 27/10 000 in the USA) [3].

Figure 2: ASIR/100 000 and ASMR/100 000 in different regions of Africa (Globocan 2008: http://www.who.int/hpvcentre[1]

Figure 3: ASIR/100 000 and ASMR/100 000 in different countries within Southern Africa (Globocan 2008: http://www.who.int/hpvcentre)[1]

In South Africa it is estimated that there are 16.84 million women over the age of 15 years who are at risk of cervical cancer. South Africa launched a pathology-based cancer registry in 1986, relying on information reported by 80 private and public laboratories. In 1986, the total number of cancers reported in women was 16 559, of which 2897 (17.4%) were new cases of histologically confirmed cervical cancer (Cancer Registry of South Africa, 1986). In 1992, the total number of reported cancers in women had increased to 25 143, and the percentage of new cases of cervical cancer remained at the same proportion as was reported in 1986 at 17.8% (n = 4 467) [4]Sitas F., Blaauw D., Terblanche M., Madhoo J., Carrara H. Incidence of Histologically diagnosed Cancer in South Africa, 1992. Published by National Cancer Registry of South Africa, South African Institute form Medical Research, Johannesburg, 1997]. There were 1105 deaths from cervical cancer recorded in 1992. It is acknowledged however, that a significant number of women with cervical cancer die without the diagnosis of cervical cancer being made, no histological sampling is performed or the disease is not registered. This is particularly true in the rural areas of South Africa and the former ‘homelands’ created by the Apartheid State prior to 1994. This suggests that the reported number of cases of cervical cancer is an underestimate of the true number of cases.

According to the 1992 South African cancer registry, the overall crude incidence rate of cervical cancer was 23/100 000 women and the Age Standardised Incidence Rate (ASIR) was 30.5/100 000 4. There were however, marked differences in incidence of cervical cancer in the various population groups. Cancer of the cervix was the most common cancer among black women (33.7% of all cancers in black women), second most common in coloured women (24.5%), followed by Asian women (10.3%) and finally by white women (3.5%). The ASIR of cervical cancer in black women was 34.6/100 000 with a lifetime risk (LR) of developing cervical cancer of 1 in 26 compared to an ASIR of 12.3/100 000 white women with an estimated 1 in 83 lifetime risk of developing cervical cancer. In

1986, the ASIR of cervical cancer for black women in SA was just below the 1992 figure at 31/100 000, suggesting that the incidence of cervical cancer in South Africa had not changed appreciably over these two time periods.

Age Specific cervical cancer rates per 100 000 women in the different ethnic groups in South Africa in 1992 showed that in all ethnic groups the rate remained very low until age 30 years after which the rates rose steadily to peak at between 50 and 79 years. The highest age specific rate for all race and age groups occurred among black women aged 60 – 64 years with a rate of 145.6/100 000.

The Age Specific Frequency of cervical cancer in 1992 follows a similar pattern with only 9.7% of cervical cancer occurring in women under 35 years of age4. The highest number of cases were diagnosed in the 50 – 54 year age group, 13.1% (n = 584), followed by the 40 – 44 age group, 12.5% (n = 560), followed by the 60 – 64 group, 12.4% (n = 555).

There is very little data on the incidence of cervical cancer in South Africa prior to the establishment of the cancer registry in 1986. However in 1960, Higginson and Oettle [Higginson J and Oettle AG. Cancer Incidence in the Bantu and ‘Cape Coloured’ Races of South Africa: Report of a Cancer Survey in the Transvaal (1953-55). J Natl Cancer Inst 1960; 24:589 – 671]5 published a survey of cancer incidence in black and coloured people in the Transvaal (one of the largest provinces in South Africa at the time) from 1953 to 1955. Their data showed that cervical cancer was by far the commonest cancer in women, accounting for 41.7% of all cancers in black women and 37% of all cancers in coloured women. These figures corresponded to an overall crude incidence rate of 31/100 000 black women and 39/100 000 coloured women. The data were based on all histological confirmed cases of invasive cervical cancer cases in the area and included rural and urban women.

Current estimates of the number of new cases of cancer of the cervix in South Africa suggest there are 5743 new cases per year and 3027 deaths from the disease [www.who.int/hpvcentre – accessed 22nd September, 2011]. These estimates were based on the pathology based data projected to the year 2008 and ‘scaled’ to the data collected by the Zimbabwe Harare City cancer registry. The Zimbabwe national cancer registry was established in 1985 and contributed data to the quinquennial IARC publication Cancer Incidence in Five Continents volume VII [Chokunonga E, Borok MZ, Chirenje ZM, Nyabakau AM and Parking DM. Chapter 31 Cancer Survival in Harare, Zimbabwe, 1993 – 1997. In Cancer Survival in Africa, Asia, the Caribbean and Central America. Edited by R Sankaranarayanan and R Swaminathan, IARC Scientific Publications no. 162, 2011]. Overall the crude incidence rate of cervical cancer in South Africa is believed to be 22.8/100 000 compared to 15.8/100 000 globally. There are no current data from a national cancer registry in South Africa, so the exact extent of the disease is unknown. Figure 4 compares the incidence rate of cervical cancer with other cancers in South African women [Data taken from www.who.int/hpvcentre, accessed 22nd September 2011].

Figure 4: Incidence of cervical cancer compared to other cancers in women of all ages in South Africa per 100 000 women

By comparison, in Europe, where there are 321.8 million women aged 15 years and older at risk, 59 931 women are diagnosed with cancer of the cervix and 28 812 die from the disease and cervical cancer ranks as the 7th most frequent cancer in Europe. America has a population of 336.5 million women aged 15 years and older and yearly 86 532 women are diagnosed with cervical cancer and 38 436 die from the disease. It ranks as the 4th most frequent cancer in women in America [1].

1.2 Rationale for a policy for prevention of cervical cancer in South Africa

The huge difference in cervical cancer incidence in developing versus developed regions is a reflection of the absence of national cervical cancer screening programs in most developing countries. Where national organized screening programs have been implemented, as was achieved in many Scandinavian countries in the second half of the last century, cervical cancer incidence and mortality were significantly reduced. Until recently, there have been no randomised trials to evaluate the impact of cervical cancer screening on cervical cancer incidence and mortality and all data on the effect of screening has come from cohort and case-controlled studies. However, the marked reduction in the incidence of and mortality from cervical cancer before and after the introduction of screening programmes in a variety of developed countries, has been interpreted as strong non-experimental support for organised cervical cancer screening programmes.

The International Agency for Research on Cancer (IARC) conducted a comprehensive analysis of data from several of the largest screening programmes in the world in 1986 and showed that well- organised screening programmes were effective in reducing the incidence of and mortality from cervical cancer [Summary Chapter: IARC Working Group on Cervical Cancer Screening. In Screening for Cancer of the Uterine Cervix. Eds: Hakama M, Miller AB, Day NE. International Agency for

Research on Cancer, Lyon, 1986 pp 133- 142]. In the Nordic countries, following the introduction of nationwide screening in the 1960s, cumulative mortality rates of cervical cancer showed a significant falling trend. The greatest fall was in Iceland (84% from 1965 to 1982) where the screening interval was the shortest and the target age range the widest. The smallest reduction in cumulative mortality (11%) was in Norway where only 5% of the population had been part of organised screening programmes [Laara E, Day NE, and Hakama M. Trends in Mortality from Cervical Cancer in the Nordic Countries: Association with organised screening programmes. Lancet 1987; May 30: 247 –1249]. The falls in Finland, Sweden and Denmark were 50%, 34% and 27% respectively. The highest reduction in cervical cancer incidence was in the 30 – 49 age groups where the focus of screening was the most intense.

In addition, the association between mortality trends and the extent of coverage of the population by organised screening was most pronounced when the proportional reductions in the age-specific rates were related to the target ages of the screening programmes. The age-specific trends indicated that the target age range of a screening programme was a more important determinant of risk-reduction than the frequency of screening within the defined age range. This finding was in agreement with the estimates of the IARC working group, that for inter-screen intervals of up to 5 years, the protective effect of organised screening was high throughout the targeted age group (over 80%) [IARC Working Group on Evaluation of Cervical Cancer Screening Programmes. Screening for squamous cervical cancer: the duration of low risk after negative result of cervical cytology and its implication for screening policies. Br Med J 1986; 293:659 – 664].

It is apparent therefore that the extent to which screening programmes have succeeded or failed to decrease incidence of and mortality from cervical cancer is largely reflected in 1] the extent of coverage of the population at risk by screening and 2] the target age of women screened and 3] the reliability of cytology services in the program.

The contrast between Finland, which had an organised screening programme and Norway, where an equivalent number of smears were performed opportunistically, indicated another important aspect of screening. Even though the difference in the total number of smears taken in the two countries was not great, the reduction in mortality was substantial for all ages in Finland, whereas in Norway, only women aged 30 – 49 years showed a fall in mortality rates: even for that age group, the fall was only half that in Finland. These data suggest that spontaneous or opportunistic screening fail to reach the most at risk women in the population, that is, middle-aged and older women of high relative risk and therefore has far less of an impact on the incidence of and mortality from cervical cancer [Hakama M, Louhivuori K. A screening programme for cervical cancer that worked. Cancer Surveys 1988; 17 (3):403 – 416].

Other reasons for the failure of opportunistic screening to reduce cervical cancer mortality include sub-optimal follow-up and management of women with abnormal smears and the lack of a co- ordinated campaign of informing and educating women about cervical cancer prevention. This results in women at high risk of disease being excluded from screening [Screening for Cancer of the Uterine Cervix. Eds: Hakama M, Miller AB, Day NE. IARC Scientific Publications no. 76, International Agency for Research on Cancer, Lyon 1986. pp 47 – 60].

Mortality from cervical cancer in the United Kingdom fell by 30% after the introduction of screening in the 1960s, however some of this decrease in mortality was attributed to falling rates in older women and could have been a cohort effect unrelated to screening [Sasieni PD, Cuzick J, Lynch- Farmery E, and The National Co-ordinating Network for Cervical Screening Working Group. Estimating the efficacy of screening by auditing smear histories of women with and without cervical cancer. Br J Cancer 1996; 73:1001 – 1005].

The need for an effectively managed national programme in the UK was realised by the mid 1980s, which led to the introduction of a computerised call and recall system for women aged between 20 and 64 years. The invitation- based system, together with target payments for general practitioners, improved population coverage from 40 – 60% in 1989, to 80% in 1992 and to 83% in 1993. In an audit of this programme in 24 self-selected districts in the UK by Sasieni et al (reference as above paragraph), it was estimated that the number of cases of cervical cancer in the participating districts would have been 57% (95% CI: 28 – 85%) greater had there had been no screening. Further they estimated that screening prevented between 1100 and 3900 cases of invasive cervical cancer in the UK.

There are many barriers to setting up national screening programs in developing countries, although in the last 15 years, new approaches and technologies have made the possibility of implementing secondary prevention screening programs in poor or low and middle income (LMIC) countries more feasible and currently there are demonstration projects in over 40 developing countries (www.iarc.org).

1.3 The Natural History of Cervical Cancer

The natural history of cervical cancer has been extensively studied in the past 30 - 40 years, and persistent infection of the cervix with certain high-risk types (also known as oncogenic types) of Human Papillomavirus (HPV) has been well established as a necessary cause of cervical cancer. Over 200 types of HPV have been identified of which around 40 infect the lower genital tract of men and women. HPV is transmitted by skin to skin contact and all forms of sexual intimacy are potential sources of transmission, including genital to genital contact and oro-genital contact.

High-risk types of HPV are identified in nearly all carcinomas of the cervix and the relative risk of developing cervical cancer associated with infection with high-risk types of HPV is higher than the risk of lung cancer associated with smoking [Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, Snijders PJ, Peto J, Meijer CJ, Munoz N. Human papillomavirus is a necessary cause of invasive cervical cancer world wide. J Pathol 1999; 189:12 – 19]. Munoz et al [ Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsague X Keertie et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Eng J Med 2003; 348: 518 – 527] pooled data from 11 case-control studies involving 1918 women with histologically confirmed squamous cell carcinoma of the cervix and 1928 control women without cervical cancer. The pooled odds ratio for cervical cancer associated with the presence of any HPV infection was 158.2 (95% CI: 113.4 – 220.6). On the basis of the pooled data, fifteen HPV types were classified as high-risk (types 16, 18, 31, 33, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82) and are considered carcinogenic.

In a meta-analysis of HPV types found in invasive cervical cancers worldwide [Clifford GM, Smith JS, Plummer M, Munoz N, Franceschi S. Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. Br J Cancer 2003; 88: 63 –73] data on a total of 10 058 cases (which included squamous cell carcinomas, adenocarcinomas and adeno-squamous carcinomas) confirmed the high prevalence of HPV in cervical cancers in different regions of the world, with HPV 16 (51%) and 18 (16.2%) being the commonest. However, more than 16 other types of HPV were also associated with cervical cancer, of which types 45, 31, 33, 58 and 52 were the most prevalent. Further, HPV type 16 was more prevalent in squamous carcinomas and HPV type 18 more prevalent in adenocarcinomas of the cervix. Overall, HPV prevalence differed little between geographical regions (83–89%) but was low compared to the almost 100% prevalence in studies that have used the most sensitive methods of detection for HPV.

A more recent publication evaluated HPV infection in paraffin-embedded samples of histologically confirmed cases of invasive cancer from 38 countries in Europe, North America, central South America, Africa, Asia and Oceania taken over a 60 year period [Silvia De Sanjose, Wim G V Quint, Laia Alemany, Daan T Geraets, Jo Ellen Klaustermeier, Belen Lloveras et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncology 2010;11:1048 – 1056]. 10 575 cases of invasive cervical cancer were included in the study and 85% (n = 8977) were positive for HPV DNA. The eight most common types of HPV detected were 16, 18, 31, 33, 35, 45, 52 and 58 and their combined contribution to the 8977 positive cases was 91%. HPV types 16, 18 and 45 were the three most common types in each type of cervical cancer (squamous cell, adenocarcinoma and adenosquamous carcinoma).

There is good evidence that HPV infection precedes the development of cervical cancer by a number of decades and that persistent infection with HPV is necessary for the development of and progression of pre-cancerous lesions of the cervix, either to higher grades of pre-cancerous disease or to cancer. Cervical cancer progresses slowly over decades from preinvasive cervical intraepithelial neoplasia to invasive cervical cancer, a process that can take 10 – 30 years [Wright TC, Kurman RJ, Ferenczy A. Precancerous lesions of the cervix. In: Blaustein’s Pathology of the Female Genital Tract. Kurman RJ (Ed.). Springer- Verlag, NY, USA (2002)]

Kjaer et al [Susanne K Kjaer, Kirsten Frederiksen, Christian Munk, Thomas Iftner. Long-term Absolute Risk of Cervical Intraepithelial Neoplasia Grade 3 or worse Following Human Papillomavirus infection: Role of Persistence. J Natl Cancer Inst 2010;102:1478 – 88] studied a cohort of 8656 women who were screened twice 2 years apart in 1991 and 1993 with cervical cytology and HPV DNA analysis by Hybrid Capture 2 (Qiagen, Gaithersburg, MD, USA) and line probe assays. The women were followed up through the Danish Pathology Data Bank for cervical neoplasia for up to 13.4 years. They found that women who had normal cytology but were positive for HPV 16 in 1993, the estimated probability of developing CIN 3 or worse within 12 years was 26.7% (95% CI:21.1 – 31.8%). The corresponding rate for those infected with HPV 18 was 19.1 % (95% CI:10. 4 – 27.3%), for HPV 31 was 14.3% (95%CI: 9.1 – 19.4%) and HPV 33 was 14.9% (95% CI:7.9 – 21.1%). The absolute risk of developing CIN 3 or worse for high risk types other than HPV 16, 18, 31 and 33 was only 6% and the risk of CIN 3 or worse if HPV DNA test was negative was 3% (95% CI: 2.5 – 3.5%). For women who tested HPV 16 positive on two occasions the risk of developing CIN 3 or worse was 47.4% over 12 years. This landmark study strongly supports the oncogenic role of infection of the cervix with high-risk types of HPV.

1.4 Understanding cervical cancer in the context of the African Continent and barriers to Cervical Cancer Screening Programs

Sub-Saharan Africa (SSA) consists of 54 countries almost all of which have the lowest ranked Human Development Index (HDI) and highest Human Poverty Indices (HPI) [www.worldbank.org]. With a total population estimated in 2008 of 812 million (404 million men and 408 million women), only 7.2% were covered by medically certified causes of death and 8.3% by population based registries. It was estimated in 2008 that there were 667 000 incident cancers diagnosed and 518 000 cancer deaths recorded i.e 78% of those diagnosed with cancer died from the disease, however reliable data on cancer incidence and survival are difficult to find in the African context [1]. Sankaranarayanan et al [reference below] evaluated cancer survival for 341 658 people diagnosed with a variety of cancers from 1990 – 2001. Two of the cancer registries were in SSA, The Gambia and Uganda, where survival was the lowest in all countries studied. No cancer exceeded a 5 year survival of greater than 22% in The Gambia, and in Uganda the similar figure was 13% except for breast cancer where survival was 46% at five years.

Moreover, access to anti-cancer therapies are very limited in almost all African countries and a WHO study in 2001 found that only 22% of African countries had access to anti-cancer drugs, compared to 91% in Europe [Rengaswamy Sankaranarayanan , Rajaraman Swaminathan, Herman Brenner, Kexin Chen, Jian Guo Chen, Stephen C K Law et al Cancer survival in Africa, Asia, and Central America: A population based study. Lancet Oncology 2010;11:165 – 173]. To illustrate the typical situation in Africa, Hanna and Kangolle [Timothy Hanna, Alfred Kangolle. Cancer control in developing countries: using health data and health services research to measure and improve access. Quality and efficiencty. BMC International Health and Human Rights 2010; 10: 24] refer to the situation in Tanzania, which is a low-income country of 42.5 million people and where 21 180 new cases of cancer were diagnosed in 2008. Nationwide there is one medical oncologist, 4 radiation oncologists, 2 physicists and 7 pathologists. There is no dedicated surgical oncology. There are two radiation machines in the country with an estimated need for 45.

The African continent has 130 medical schools located in 41 countries, but facilities for training in cancer diagnosis and management are found mainly in North Africa (Egypt, Morocco, Algeria) and South Africa with limited facilities in Nigeria, Libya and Zimbabwe. In 2007 it was estimated that the per capita expenditure on health in the USA was $6 096 compared to $32 in SSA, most of which were donor dollars [Independent Evaluation Group Studies. Annual Review of Development Effectiveness: Achieving Sustainable Development. 2009 World Bank].

Further, there is a great shortage of trained health care personnel in Africa where there is also a very large ‘brain drain’ or exodus of trained personnel to other more attractive continents. The World Health Organisation (WHO) estimated in 2006 that Africa has a needs-based shortage of 818 000 health care professionals (meaning doctors, nurses and midwives) based on a country needing 2.28 health care professionals per 1 000 population) [WHO, Working Together for Health: the World Health Report 2006 (Geneva, WHO, 2006)]. In a study by Scheffler et al [Richard M. Scheffler, Chris Brown Mahoney, Brent D. Fulton, Mario R. Dal Poz and Alexander S. Preker. Estimates of Health Care Professional Shortages in Sub-Saharan Africa by 2015. Heath Affairs 2009;28(5):849 – 862], they estimated that for 31 SSA countries in 2015 the shortage of health care professionals will be 792 000 and the estimated wage bill necessary to eliminate the shortage is approximately $2.6 billion.

2.0 Impact of Human Immune Deficiency Viral (HIV) Infection

Adding to the complexity of the challenges facing SSA (ranging from environmental disasters, to competing health needs such as malaria and maternal mortality, endemic civil strife, war, lack of safe water and sanitation to name a few) has been the HIV/AIDS epidemic, where 70% of the world’s cases of HIV are diagnosed (www.unaids.org). It has been well known that HIV infection increases the risk of developing certain cancers and Kaposi Sarcoma, Non-Hodgkin Lymphoma and Cervical cancer have been classified as AIDS defining diseases since 1993 [1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults MMWR Recomm Rep 1992;41:1 – 19]. Women infected with HIV have an increased risk of being infected with HPV and are therefore considered at higher risk for cervical cancer. However, the expected increase in women diagnosed with cervical cancer in Africa during the HIV pandemic has not been convincingly observed, most likely due to most at-risk women dying from other opportunistic infections prior to developing cervical cancer or its precursors. In the era of anti- retroviral medication, this scenario is expected to change dramatically.

South Africa has the largest expanding HIV burden in the world and it is estimated that 5.7 million South Africans are currently living with HIV/AIDS, of whom 60% are women [UNAIDS, Country Progress Indicators. In: Report on the global AIDS epidemic. Geneva: UNAIDS 2008]. In 2008 the adult prevalence in the age group 15 – 49 years was estimated at 16.9% [Shishana O, Rehle T, Simbayi LC, Zuma K, Jooste S et al. For the SABSSM III Implementation team. South African national HIV prevalence, incidence, behaviour and communication survey 2008: A turning tide among teenagers? Cape Town:HSRC Press, 2009].

Studies have consistently shown higher prevalence of HPV infection, persistent infection with oncogenic HPV, infection with multiple types of HPV and higher prevalence of cervical cancer precursors in HIV infected women [Joel M Palefsky, Howard Minkoff, Leslie A Kalish, Alexandra Levine, Henry S Sacks, Patricia Garcia Diljeet Singh, Kathryn Anastos, Donald Hoover, Robert Burk, Qiuhi Shi, Louis Ngendahayo, et al. Human Papillomavirus Infection and Cervical Cytology in HIV- infected and HIV-uninfected Rwandan Women. JID 2009;199(12):1851-61 AND Tedd V Ellerbrock, Mary Ann Chiasson, Timothy J Bush, Xiao-Wei Sun, Dorothy Sawo, Karen Brudney et al. Incidence of Cervical Squamous Intraepithelial Lesions in HIV-infected Women. JAMA 200;283: 1031- 1037 AND, Tiffany G Harris, Robert D Burk, Joel M Palesky, L Stewart Massad, Ji Yon Bang, Kathryn Anastos et al. Incidence of Cervical Squamous Intraepithelial Leions Associated with HIV serostatus, CD4 Cell Counts, and Human Papillomavirus Test Results. JAMA 2005: 293: 1471- 1476 AND Diljeet Singh, Kathryn Anastos, Donald Hoover, Robert Burk, Qiuhi Shi, Louis Ngendahayo, et al. Human Papillomavirus Infection and Cervical Cytology in HIV-infected and HIV-uninfected Rwandan Women. JID 2009;199(12):1851-61].

The Rwandan Women’s Interassociation Study and Assessment (RWISA) is an observational prospective cohort study of 710 HIV positive women and 226 HIV negative Rwandan women, enrolled into the study in 2005 [Diljeet et al – see above]. The prevalence of HPV was significantly higher in the HIV positive group and adjusted for age (25 – 34 years 75% vs 29%; 35 – 44 years 64 vs 7%; 45 – 54 years 57% vs 13% and over 55 years 38% vs 0%). In addition 46% of HIV positive women had high-risk types of HPV and 35% were infected with multiple types and in turn, this was associated with higher risk of abnormal cytological findings.

Denny et al [Denny L, Boa R, Williamson AL, Allan B, Hardie D, Ress S, Myer L. Human papillomavirus infection and cervical disease in human immunodeficiency virus-1 infected women. Obstet Gynecol 2008 111(6):1380 -87] found that 68% of their cohort of HIV positive women were infected with high-risk types of HPV using HC II as the HPV DNA test, and 94% of these infections persisted over a 36 month period, with only 6% of women clearing infections. In another South African study of 5595 women aged 35 – 65 years of age followed for 36 months, 577 women were HIV positive at enrolment and subsequently 123 women seroconverted. Among women who underwent HIV seroconversion, HPV prevalence was 20.3% before seroconversion, 23.6% at seroconversion and 49.1% after seroconversion. HIV seroconversion was associated with newly detected HPV infection and increased risk of low-grade cytological abnormalities compared with HIV negative women [Wang C, Wright TC, Denny L, Kuhn L. Rapid rise in detection of human papillomavirus (HPV) infection soon after incident HIV infection among South African women. J Infect Dis 2011;203(4):479 – 86].

A recent article reported on a case controlled study from Cote d’Ivoire of 132 women with invasive cervical cancer and 130 control women who had normal Pap smears. They found a positive association between HIV infection and women with cervical cancer and concomitant high-risk type of HPV infection with an OR of 3.4 (95% CI 1.1 – 10.8) [Georgette Adjorlolo-Johnson, Elizabeth R Unger, Edith Boni-Ouattara, Kadidiata Toure-Coulibaly, Chantal Maurice, Suzanne D Vernon et al. Assessing the relationship between HIV infection and cervical cancer in Cote d’Ivoire: A case-control study. BMC Infectious Disease 2010;10: 242 – 250].

The high prevalence of cervical abnormalities in HIV positive South African women has major health planning and resource implications, particularly as access to anti-retroviral therapy in HIV positive women increases [Moodley JR, Constant D, Hoffman M, Salimo A, Allan B et al. Human papillomavirus prevalence, viral load and pre-cancerous lesions of the cervix in women initiating highly active anti-retroviral therapy in South Africa: a cross-sectional study. BMC Cancer 2009;9: 275]. Ideally, cervical cancer prevention services should be integrated into the platform of HIV/AIDS care and treatment programs but this happens only sporadically and inconsistently and one study in Cape Town showed that between 13 and 60% of HIV positive women were being offered cervical cancer screening [Batra P, Kuhn L, Denny L. Utilisation and outcomes of cervical cancer prevention services amongh HIV-infected women in Cape Town. S Afr Med J 2010;100(1):39 – 44].

Cytological screening is equally effective in HIV positive and HIV negative women. The current practice in SA is to offer annual screening to HIV positive women who are immune compromised (CD4 < 350) although the evidence for this, as well as starting to screen HIV positive women at a younger age is not very strong at this point. The recommendation for the screening of HIV positive women is addressed below.

3.0 Proposed Cervical Cancer Prevention Policy for South Africa - Assumptions

This policy is based on the following assumptions:

1] Screening older women (> 30 years) is the most cost-effective and will have the greatest impact on the cumulative incidence of cervical cancer compared to frequent screening of younger women (eg. Pregnant women attending ante-natal services)

2] Coverage of greater than 70% of the population should be the target and that the widest possible coverage of the targeted population is more important for the prevention of cervical cancer than the interval of screening

3] Longer screening intervals, up to 10 years using cytology, have been shown to reduce cervical cancer by 2/3’s in well organised national programmes with built-in call and recall. Using a more sensitive test for screening, such as HPV DNA testing will allow safer and longer screening intervals and may be the screening test of choice depending on resources, laboratory infrastructure and costs of the test.

4] Using mathematical modelling of 8 successful screening programs in the 20th century, IARC estimated that with coverage of 100% of women aged 35 – 65 years with cytology, and performing a Pap smear every year with follow up of all women with abnormal cytology, would reduce the cumulative incidence of cervical cancer by 93%, and each woman would undergo 30 Pap smears in a lifetime. Assuming similar coverage, the reductions in cervical cancer screening 3 yearly would be 91% with each woman undergoing 10 smears in a lifetime. The similar figures for intervals of 5 years were 85% (6 smears in a lifetime) and 10 yearly 67% with women undergoing 3 smears in a lifetime. These data were based on cytology-based screening programs and showed very clearly that coverage is critical and more important than screening intervals in ASYMPTOMATIC older women and even long intervals between screening could reduce the incidence of cervical cancer.

5] Cervical cancer screening is designed for ASYMPTOMATIC women – women who are symptomatic (abnormal vaginal discharge, bleeding, pain etc), undergoing surgery (such as a tubal ligation or hysterectomy) should have a ‘work up’ or diagnostic cervical screening test regardless of age or recent screening history.

5] Cervical cancer screening will be offered as a free service at primary health care clinics in all centres of South Africa to all women in the target age range i.e. 30 years and older. Appropriate training and provision of equipment will be provided to health care workers to ensure quality screening may be performed.

6] A functional referral and triage system will be created whereby ALL women will receive the results of their screening tests, whether positive or negative. For women with positive (or abnormal screening tests), appropriate referral systems will be instituted for either further triage of the test or for definitive treatment.

7] Treatment facilities will be made available to women in an accessible and women friendly manner and will ensure not only appropriate treatment is performed but that long term post treatment follow up (at least 5 years) is provided to detect and treat recurrences or failures of treatment.

8] Facilities for the treatment of screen detected cervical cancers will be made available and accessible to all women and clear referral patterns established timeously.

9] Women attending for screening will be encouraged to undergo HIV testing, be given information on symptoms and how to prevent other STIs, contraception and general health information such as self breast examination for cancer and the symptoms associated with other cancers.

10] All primary care clinics will keep a register of all women screened, either electronically or in a paper format, and this register will record date of the screening test, the result of the test both in terms of diagnosis and adequacy, date the result is given to patient, and action taken. It will also be incumbent on the primary care facility to liaise with the relevant colposcopy clinic to ensure that women requiring colposcopy attend for their appointment. If women do not attend, a system relevant to the particular health facility must be created to ensure that women with abnormal cervical smears are identified, informed and that they attend their assigned colposcopy appointment.

11] How appointments are made for further triage or for colposcopy will be site and situation specific (Reference to the CHIP manual should be made here).

12] All women undergoing cervical cancer screening will be offered HIV testing and all women undergoing HIV testing will be offered cervical cancer screening, age appropriate.

13] Built into the design of the Cervical Cancer Policy of South Africa will be a policy on:

 Training of health care workers (including community health care workers to track women who need colposcopy)

 Creation of adequate, accessible and well equipped clinical facilities, laboratory infrastructure and communication strategies between the different sectors involved in cervical cancer prevention

 Monitoring and Evaluation of the program

 Establishment of a South African Cancer Registry

3.1 Choice of Screening test: Cytology

Historically cytology screening, where used correctly, has been known to reduce cervical cancer significantly. It is currently the only FDA approved stand alone primary test for cervical cancer, be it conventional or liquid-based cytology (LBC). South Africa has a well established network of 12 cytology laboratories nationally which serves all rural and urban primary care clinics (Irene Le Roux, NHLS, personal communication). Currently there are 120 suitably qualified cytotechnologists performing screening services as well as 5 focal point scanning systems. Each of these systems, if used to full capacity, equates to around 3 extra screeners – that is 15 in total. In 2010 the NHLS laboratories processed nearly 1 million smears of which greater than 680 000 were gynaecological smears. The current cost of a Pap smear to the South African government is R55. However, despite this low cost, large numbers of eligible women are not being screened and the incidence of cervical cancer in South Africa remains very high. Our focus on treating abnormal lesions is also abysmal and large numbers of screened women never reach the appropriate level of care.

Major problems with cervical cytology include:

 Poor quality smears taken by clinicians either through poor training or lack of proper equipment, resulting in either false positive or false negative smears. These smears also need to be repeated adding considerably to the costs of screening.

 Failure to deliver the smear to the laboratory (getting lost), failure to correctly label the smear or to receive the result of the smear timeously (in some facilities it can take 6 months for a patient to receive a result of a smear).

 Need for the smear to be read in a laboratory with all the attendant costs, training, built-in quality control and retention of quality screeners.

 Ensuring that the smear a] arrives at the laboratory, b] the smear is properly processed and interpretable, c] the smear result is communicated to the patient and d] that appropriate action is taken if the smear is either inadequate or abnormal.

 Referral for colposcopy – very high default rates are reported from many primary care facilities with some reporting that only 20% of women with abnormal smears ever receive colposcopic examination and appropriate treatment and follow up.

 Need for an anatomical histology laboratory infrastructure to interpret the specimen used to either diagnose (punch biopsy) or treat the cervical abnormality (LLETZ, LEEP or cone biopsy) and ensure that the patient is followed-up post diagnostic intervention or treatment (this is an important part of the puzzle as failure rates up to 20% are reported from some institutions and in HIV positive women, failure rates of 50% are reported. These women need repeat colposcopy and further treatment be it LLETZ, cone biopsy or hysterectomy in some instances). The screening process MUST be followed to the point that the screened individual is DISEASE-FREE.

 Providing adequate treatment facilities and follow-up of treated women is one of the WEAKEST links in the whole cytology-based screening programme that exists in SA today

3.2 Recommendations for cytology-based screening

Poor quality cytology is almost as bad as no screening at all and is a terrible waste of health dollars. It is suggested in this protocol that WHERE FACILITIES ARE APPROPRIATE and cervical cytology infrastructure is functional that cervical cytology continued to be used and that the NHLS adopt the Bethesda system for reporting. Suggested approach would be:

1. Cytology screening is reserved for women who are ASYMPTOMATIC and who have a macroscopically normal cervix. An abnormal looking cervix warrants referral to the next highest level of care and it is inappropriate to perform a smear on a cervix which is macroscopically abnormal. If a speculum is not available at a primary care level, then eligible women should be referred to a facility where a proper speculum examination can be performed.

2. Inadequate smears should be repeated in 3 months. If still inadequate the reason should be investigated and appropriate intervention instituted. An adequacy rate of over 80% should be expected and a figure less than that should be investigated. Adequacy includes sufficient

squamous cells on the slide, adequate number of endocervical cells as well as properly fixed slides using cytofix to prevent inaccurate interpretation of the slide by the cytotechnologist. It must be recognised that screening post menopausal women often results in inadequate smears and that pre-treatment with topical premarin prior to repeat cytology may render the smear more readibly and accurately interpreted.

3. LBC is only preferable to conventional cytology to reduce inadequacy rates, is more expensive than conventional cytology and in many randomised trials has not been shown to be superior to conventional cytology, especially in poorly screened populations where lesions tend to be bigger and more easily detected with conventional cytology. LBC does however offer other advantages, such as concomitant HPV DNA testing or testing for other STIs – this will be addressed below but should be seen as a resource issue. LBC in the future may also be used for automated screening.

4. Asymptomatic women should be offered 3 free smears in a lifetime beginning at age 30. If during the screening interval the woman becomes symptomatic (discharge, abnormal bleeding or anything else untoward) the patient should be advised to return immediately for a gynaecological examination. If asymptomatic women wish to be screened more frequently than 10 yearly they should be offered a smear but should be charged for it, as long as she remains asymptomatic.

5. If HIV status is known and is positive, screening should begin at age 25 and as long as is normal should be repeated 3 yearly. For abnormal smears in HIV positive women they should follow the same protocol as will be articulated below for HIV negative or HIV unknown status women.

6. Cytology forms should be filled out with meticulous attention to detail, particularly ensuring that the patient contact details are all available and accessible. Clinical data is also very useful information for the screening technologist. The form should also clearly indicate whether the smear is for diagnostic (‘work up’) or for screening purposes.

3.3. Suggested action in response to the cytology diagnosis in women with macroscopically normal cervices and over the age of 30 years (these recommendations refer to HIV positive, HIV status unknown and HIV negative women):

1. Inadequate Pap smear: repeat 3 months or give topical premarin (estrogen) in post menopausal women or women with clinically atrophic cervices. Or if inadequate smear due to gross cervicitis, treat with triple antibiotic therapy and repeat Pap in 3 months. It is preferable not to do Paps on menstruating women however, a woman who presents for a Pap smear who is bleeding should have her cervix examined either at that visit or a week later to ensure that the bleeding is not related to an abnormal cervix.

2. ASCUS (Atypical squamous cells of unknown significance):

a. Repeat x 3 at 6 month intervals and if persists refer for colposcopy

b. There is also good randomised evidence that performing a HPV DNA test for high- risk types of HPV in these women is helpful for triage. Women who are high-risk HPV

DNA positive and have an ASCUS Pap smear should be referred for colposcopy rather than repeat cytology. This approach i.e using HPV DNA testing will be resource dependent but has been shown in large clinical trials to be a cost-effective method of triaging ASCUS cytology

3. ASC-H (Atypical squamous cells but HSIL cannot be excluded):

a. Refer colposcopy at next available visit (treat as HSIL – see below)

4. AGS (Atypical glandular cells) NOS:

a. treat empirically for endocervical infection with triple antibiotic therapy and repeat Pap in 6 weeks (if cytological abnormality persists, refer colposcopy)

5. AGS (Atypical glandular cells suspicious of in-situ or carcinoma):

a. Urgent colposcopy referral

6. HSIL (High grade squamous intra-epithelial lesion):

a. Immediate referral for colposcopy but not urgent

7. LSIL (low grade squamous intra-epithelial lesion):

a. repeat x 2 at 6 monthly intervals – if persists refer colposcopy. If one LSIL pap followed by normal Pap, repeat Pap yearly for 3 years and only discharge if 3 normal consecutive Paps

b. If LSIL confirmed on colposcopy, each unit should define threshold for treatment, patient availability for follow up etc

8. Any suspicion of cancer:

a. Urgent referral for colposcopy

9. Endometrial cells found in a Pap in a woman over the age of 40 years requires investigation for primary endometrial disease

4.0 Colposcopy Clinic

All women referred to colposcopy clinic should be recorded in an appropriate register at the primary care clinic and the date of arrival or non-arrival at the colposcopy clinic recorded. A system appropriate to each facility should be designed to ensure that women who do not arrive for their appointment can be contacted and a new appointment given. Failure to perform colposcopy on a woman with an abnormal Pap smear is a serious waste of health dollars and makes a mockery of the screening programme.

All colposcopy clinics should have a proforma or a standardised letter to give to the patient AND to post (or fax or email) to the appropriate clinic giving the findings at colposcopy and the action taken and the action expected for the next years. Included should be the date of the patient’s next appointment.

It is recommended that a “see and treat” approach be taken at colposcopy i.e. if a HSIL lesion is detected that it is treated without confirmatory biopsy in order to avoid excessive visits to the clinics, reduce waiting times, as well as costs associated with laboratory procedures. However, regular training and audit of colposcopists should be undertaken in all clinics and close collaboration between cytologists, histopathologists and colposcopists is highly recommended.

It is strongly recommended that colposcopy services be dramatically increased throughout South Africa and that a cadre of career medical officers be taught how to perform colposcopy and manage cervical abnormalities. There is a CRITICAL shortage of colposcopy services nationally, with facilities almost exclusively found in urban areas. It is not recommended that colpsocopy is taught to doctors or nurses working on a rotational basis. Good colposcopy requires practice and audit and poorly performed colposcopy is likely to result in cancers being missed. Colposcopy requires a degree of ‘verticalisation’ within the health care system and should not be performed by inadequately trained personnel. It is important to add that high level nurse practitioners can also be taught to perform colposcopy but such personnel should be allowed to practice their skills on a regular basis.

4.1 Integration of screening

Failure of communication between the different ‘arms’ of the screening process causes a great deal of waste and allows women with abnormalities to fall through the cracks. Screening without a STRONG, RELIABLE AND ACCESSIBLE system for treatment is a waste of time. Reducing cervical cancer relies on the removal of abnormal cells from the cervical transformation zone. It cannot be emphasised strongly enough that preventing cervical cancer requires:

5.0 Alternative approaches to cervical cancer prevention

The many challenges and difficulties imposed by a good quality cytology-based cervical cancer programs has stimulated a number of large research projects to evaluate alternative approaches to the use of cytology. Most of these studies have taken place over the last 15 years and many have shown great promise. Two of the most researched alternatives are Visual Inspection with Acetic Acid (VIA) and HPV DNA testing for high-risk types of HPV infection of the cervix.

5.1 VIA

VIA involves washing the cervix with a solution of 3 – 5% acetic acid and training a primary health care worker to examine the cervix with a bright light to detect what are known as ‘aceto-white’ lesions of the cervix, usually clustered around the transformation zone of the cervix. The advantage of VIA is that it gives an immediate result and lends itself to immediate treatment of lesions where appropriate. Many thousands of women have been included in cross-sectional studies of VIA and the performance characteristics, certainly in terms of sensitivity have been relatively equivalent to cytology, although with a lower specificity and positive predictive value i.e. large numbers of women with positive VIA tests do not have disease and are subjected to unnecessary treatment.

Two seminal randomised trials comparing VIA to cytology and HPV DNA testing or to no testing or treatment of abnormal screening tests, have shown rather disappointing results for VIA. Denny et al randomised 6555 unscreened women aged 35 – 65 years, to three groups: HPV and treat if positive (using cryotherapy), VIA and treat if positive or to delayed treatment regardless of the screening result. All women underwent colposcopy and biopsy 6 monthly for 36 months. At 36 months the reduction in precancerous lesions in the VIA group was 32% for HSIL (or CIN 2 or 3) compared to the control group and in the HPV and treat group the reduction was 73% for HSIL (in other words more than twice as effective) [Lynette Denny, Louise Kuhn, Michelle de Souza, Amy E Pollack, William Dupree, Thomas C Wright Jr Screen-and-Treat Approaches for Cervical Cancer Prevention in Low Resource settings JAMA 2005;294:2173 – 2181 and Denny L, Kuhn L, Hu CC et al. Human papillomavirus – based cervical cancer prevention: long term results of a randomised trial. J Natl Cancer Inst 2010;102:1557 – 1567).

In another trial conducted in India [Sanakaranararyanan R, Nene BM, Shastri SS et al. HPV screening for cervical cancer in rural India. N Engl J Med 2009;360:1385 – 1394], compared a single round of VIA, cytology, HPV DNA testing or no screening on cervical cancer mortality in a trial involving 132 000 women aged 30 – 59 years. No significant reduction in cervical cancer mortality was reported after VIA and treat in this study, whereas HPV DNA screening was followed by a significant 48% reduction in mortality from cervical cancer compared with the control group. During the 8 year follow up period, 25 out of 23 032 women who tested negative with VIA developed cervical cancer compared with eight of the 24 380 who tested negative for HPV DNA testing.

In contrast to these two studies, a routine ‘screen and treat’ programme using VIA screening and cryotherapy in various areas of Thailand has been ongoing since 2005. So far more than 800 000 women have participated in these programmes but data on the impact of this approach on cervical cancer incidence from reputable cancer registries is still awaited. However, the incidence rate of cervical cancer increased by 3 fold in 2006 compared to 1997 in one province in Thailand, and this has been attributed to increased case finding and VIA coverage in the area [Chumworathayi B, Blumenthal PD, Limpaphayom KK et al. Effect of single-visit VIA and cryotherapy cervical cancer prevention program in Roi Et, Thailand. A preliminary report. J Obstet Gynaecol Res 2010;36:79- 85].

The advantages and disadvantages of VIA- based programs include the following:

1. Low technology and low cost and gives an immediate result and can be performed by mid to low-level health care practitioners, without a prolonged period of training.

2. While the test characteristics of VIA do not stand up to scrutiny when subjected to randomised controlled trials, the test is better than no screening at all and can be readily set up in very low resourced settings.

3. Setting up VIA and treat programs allows for the creation of an infrastructure for older women (> 30 years) and once a more reliable and affordable test is developed, should allow for the seamless introduction of a more effective screening program based on a more accurate screening test. Creating infrastructure should be viewed as a KEY activity in setting up cervical cancer screening programs.

4. VIA and treat program have allowed for greater number of cases to be detected early and thus the possibility of cure due to treatment of early disease.

5. The main disadvantages include:

a. Poor quality control of the screeners (the only method is the use of digital photography which has been used with some success in a large project in Zambia where even cell phone photographs have been sent to a central clinic for advice and confirmation of the diagnosis. Parham and his group in Lusaka, Zambia have to date screened over 50 000 women using VIA, however true impact on cervical cancer incidence is still awaited [Mwananhamuntu MH, Sahasrabuddhe VV, Kapambwe S, Pfaedler KS, Chibwesha C, Mudenda V et al. Advancing cervical cancer prevention initiatives in resource-constrained settings: insights from the Cervical Cancer Prevention Program in Zambia. PLoS Med 2011;8(5):e1002032Epub 2011 May 17])

b. Necessity of on-going training of screeners and the fact that most of the data has come from well controlled and supervised research projects and the true efficacy of the test under field conditions without stringent quality control and regular retraining of screeners remains to be determined

c. Randomised data show a minimal impact on cervical cancer incidence and no impact on cervical cancer incidence or mortality.

5.2 RECOMMENDATION:

VIA programs in South Africa should only be used to create a screening infrastructure with a clear understanding that it is an inferior screening test and impact on the cumulative incidence of cervical cancer is likely to be minimal. Training should follow international trends and quality control introduced using digital photography.

6.0 HPV DNA testing

Similar to ‘VIA and treat’, many thousands of women have been subjected to screening using HPV DNA testing. To date three types of HPV tests are FDA approved: 1] Hybrid Capture 2 (Qiagen,

Gaithersburg,MD,USA), which detects 13 oncogenic types of HPV (16,18,31,33,35,39,45,51,52,56,58,59,68) and uses full genome probes complementary to HPV DNA, specific antibodies, signal amplification and chemiluminescent detection, 2] the Cervista HPV high risk test which detects 14 high risk types using signal amplification method for detection of specific nucleic acid sequences. Neither of the above two tests differentiate between single HPV genotype infections and multiple concurrent HPV genotype infections and neither is able to quantify viral load. The third test, Cervista HPV 16/18 detects only types 16 and 18 which are the genotypes most commonly associated with cancer and uses a similar methodology as the Cervista HPV HR assay.

6.1 There is a substantial literature on HPV DNA testing that suggests that testing for high-risk types of HPV DNA testing can be used as a primary screening test:

 HPV DNA testing over the age of 30 years is a cost-effective and accurate means of primary screening. Cuzick et al showed that HPV DNA testing in over 60 000 women aged 30 – 60 years had a sensitivity for detecting CIN 2/3 or greater of 96.1% compared to cytology at 53.0%, although the specificity was much lower (90.7% versus 96.3% respectively)[ Cuzick et al. Overview of the European and North American studies on HPV testing in primary cervical cancer screening. Int J Cancer 2006;119(5): 1095 – 1101]

 Katki et al [Katki HA, Kinney WK, Fetterman B, Lorey T, Poitras NE, Cheung L et al. Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice. Lancet Oncol 2011 Aug:12(8):722] recently published on a study of women undergoing concurrent testing for human papillomavirus and cervical cytology in a population-based study in routine clinical practice. They assessed the 5 year cumulative incidence of cervical cancer and CIN 3 or worse in 331 818 women aged 30 years and older who underwent co-testing with cytology and HPV DNA testing (using HC II). Of the 315 061 women who had negative HPV DNA tests, the 5 year cumulative incidence of cancer was 3.8 per 100 000 women per year. For women with both negative on PAP and HPV DNA testing the rate was 3.2/100 000. For women negative on Pap testing the rate was 7.5/ 100 000, almost twice that of women negative for HPV DNA testing. These data again strongly support the use of HPV DNA testing as a primary screening test, particularly because of the very high negative predictive value of HPV DNA testing. A single negative HPV DNA test was sufficient to reassure against a diagnosis of cervical cancer or CIN 3+ over 5 years. Further, incorporating HPV testing with cytology resulted in earlier identification of women at high risk of cervical cancer, particularly adenocarcinomas. This study suggested that testing with HPV DNA testing without cytology might well be sufficiently sensitive for primary screening for cervical cancer.

 These data, combined with the studies in South Africa and India (references above) strongly suggest that HPV DNA testing could be used as a primary screening test. The issues however are how to manage women with a positive HPV DNA test with a negative Pap smear or how to triage those women with a positive HPV DNA test who are truely destined to develop a precancerous or malignant lesion of the cervix, as opposed to having a transient or clinically non-significant positive test. A great deal of research is currently going into developing a triage test to improve the specificity of HPV DNA testing – to prevent overtreatment which has its own problems and may increase anxiety in women.

 Proof of HPV DNA testing on reducing the incidence of and mortality from cervical cancer is slowly accruing and the Dutch government recently introduced HPV DNA testing as part of its routine screening program in June 2011. The Health Council of the Netherlands, [Population Screening for cervical cancer. The Hague: Health Council of the Netherlands, 2011 publication no 2011/07] recommended that testing for high-risk types of HPV DNA should replace cytology as the primary screening method as it affords better protection against cervical cancer than cytology. Further, the committee recommended that triage of women with positive HPV DNA tests is an essential element of the screening process, particularly to prevent unnecessary referral for colposcopy. The committee currently recommends that women with positive HPV DNA tests undergo cytology and that the same sample taken for the HPV DNA test should used for the preparation of the Pap smear, to prevent an unnecessary test or visit to the clinician. If the cytology test is negative the patient should be offered 6 – 12 month follow up with cytology or HPV DNA testing. If the Pap smear is abnormal, women should be referred for colposcopy to make a diagnosis or for treatment.

 Because HPV DNA testing leads to an earlier detection of CIN 3+ the screening interval can be extended and the Health Council of the Netherlands believes that the number of lifetime screens offered to women should be reduced from 7 to 5. Women will be tested at age 30, 35, 40, 50 and 60 years in the Netherlands from now on.

 This program should provide ‘real’ data on the impact of HPV DNA testing on cervical cancer incidence and mortality as opposed to the data generated by mathematical modelling.

6.1. Major reservations of using HPV DNA testing as a primary screening test in the South African context include:

. Cost (currently around R400 per test although this could be negotiated with the manufacturer and a substantially lower cost could be agreed upon)

. Setting up laboratories able to perform HPV DNA testing

. Low specificity and low positive predictive value of current commercially available tests which will lead to over treatment and referral of larger numbers of women for colposcopy, a service which already is unable to cope with the number of women with abnormal Pap smears

. High levels of HPV DNA positivity in HIV positive women, which will lead to greater use of resources such as colposcopy and possible overtreatment

. Linking HPV DNA testing to immediate treatment will have a significant impact on the incidence of cervical cancer and its precursors, but an appropriate infrastructure would need to be created to accommodate such a program, including training of health care personnel and educating the public

6.2 Other uses of HPV DNA testing

 HPV DNA testing for the triage of women with ASCUS cytology [The Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study (ALTS) Group. Human papillomavirus testing for triage of women with cytologic evidence of low-grade squamous intraepithelial lesions: baseline data from a randomised trial. J Natl Cancer Inst 2000;92(5):397-402 AND Wright TC Jr, Schiffman M, Solomon D, Cox JT, Garcia F, Goldie S, et al. Interim Guidance for the use of Human Papillomavirus DNA Testing as an Adjunct to Cervical Cytology for Screening. Obstet Gynecol 2004;103:304-9] has been shown to reduce referral for colposcopy and to more accurately triage women at risk of cervical cancer and its precursors compared to repeat cytology. However, in a South African context, this is most likely unaffordable and concurrent testing is not recommended at this point.  HPV DNA testing for women post treatment to detect failures of treatment or recurrences has been shown to be more sensitive than cytology or VIA [Paraskevaidis E, Arbyn M, Sotiriadis A, Diakomanolis E, Martin-Hirsch P, Koliopoulos G. The role of HPV DNA testing in the follow-up period after treatment for CIN: a systematic review of the literature. Cancer Treat Rev 2004;30:205-11.]  Self testing has gained much interest in recent years, particularly for women who are reluctant to undergo gynaecological examinations. Results of self versus clinician testing have varied from study to study. Beilinson et al [Beilinson JL, Du H, Yang B, Belinson SE, Pretorius RG, Yi X, Castle PE. Improved sensitivity of vaginal self-collection and high-risk human papillomavirus testing. Int J Cancer 2011 May 31 doi:10. 1002/ijc.26202] recently published on a study of 10 000 women who were screened with cervical cytology and high- risk HPV testing of vaginal self collected and endocervical physician collected specimens. Women were randomly assigned to use either a novel self collection device (POI/NIH) or a conical shaped brush (Qiagen) and the samples were tested using Cervista. Self testing was found to be as good as clinician testing. Taylor et al in a large South African screening trial [ Taylor S, Wang C, Wright TC, Denny L, Kuhn L. A comparison of human papillomavirus testing of clinician –collected and self-collected samples during follow-up after screen and treat. INt J Cancer 2011, 129(4):879 – 86] found that the sensitivity of HPV testing using HC II in self-collected specimens was significantly lower among treated versus untreated women (55% versus 78%; p = 0.01). HPV testing of clinician –collected samples detected the most cases of CIN 2+ among both treated (85%) and untreated (91%) women. Cytology detected 76% of cases among both treated and untreated women using ASCUS as the cut- off.  Subsequent to the South African study, Beilinson and Gravitt et al [Gravitt PE, Beilinson JL, Slameron J, Shjah KC. Looiking ahead: a case for human papillomavirus testing of self- sampled vaginal specimens as a cervciccal screening strategy. Int J Cancer 2011; 129(3)517- 27] have made a strong case for the use of self sampling , with results suggesting that self- sampling has a sensitivity better than both cytology and VIA. They argue that self sampling allows for primary screening to move from the clinic to the community, and that strong and effective efforts at mobilizing communities to take control of cervical cancer screening.

7.0 New HPV DNA tests 7.1 careHPV

A new HPV DNA test is currently under development called the careHPV (Qiagen, Gaitherburg, MD, USA) which uses a signal-amplification assay that detects 14 high risk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68). The test only requires 25 x 50 cm work space, does not require electricity or running water and takes approximately 2.5 hours to perform [Qiao YL et al. A new HPV DNA test for cervical cancer screening in developing regions: a cross sectional study of clinical accuracxty in rural China. Lancet Oncol 2008;9(10):929 – 36]. Qiao et al performed a cross-sectional study of 2 388 previously unscreened women aged 30 – 54 years and showed a sensitivity of careHPV for CIN 2 + to be 90% (95% CI: 83 – 97%) with a specificity of 84.2% (95% CI:72.3 – 90.5%) on clinician provided specimens. For self collected specimens the sensitivity of careHPV was 81.4% and the specificity was 82.4%. The was compared to VIA which had a sensitivity of 41.4%. While the concept of ‘screen and treat’ using careHPV has many advantages, the actual implementation requires many issues to be ironed out that include:  How many tests can be performed per day – the current protocol enables 80 tests to be performed per run and this would overwhelm the health personnel. So smaller number of tests would need to be performed to make it feasible to treat women on the same day.  Women being prepared to be wait 3 hours and then be treated on the same day without the opportunity to consult with family members (this is critically important in an African context)  Complications of treatment are minimal and acceptable to women

7.2 HPV Genotyping

Currently Cervista is the only FDA-approved HPV genotyping test that identifies only 16 and 18. There are many other tests on the market but proper validation and impact on cervical cancer incidence and mortality is awaited.

7.3 Screening for HPV integration into the host genome

Tests that identify the integration of the HPV genome into the host cell DNA are in development and preliminary data suggest that these tests may significantly improve the specificity of HPV DNA testing by identifying those women who are truly destined to develop cervical cancer. Data from these tests are awaited.

8.0 Key components of a screening program include the following:

 Client recruitment  Screening services at primary level  Services for the screening test chosen (VIA, Cytology, or HPV DNA testing)

 Client management at primary care level which includes meticulous record keeping, tracking of women with abnormal screening tests, liaison with colposcopy clinics and tertiary institutions where women with cancer are treated  Colposcopy treatment and standardized colposcopy treatment algorithms with linkage of colposcopy acquired histology to cytology data base  Clearly defined system of monitoring and evaluation of the screening program  Long term planning, training, audit and budgeting

8.1 Enhancing community awareness and participation includes the following:

 Provide information on cervical cancer through imbizos, community dialogue and support groups that use participatory methods  Development of appropriate information, educational and communication (IEC) materials that facilitate dialogue, peer counseling within community groups and with health facilities  The engagement of the broader public through regular radio and TV broadcasts on cervical cancer prevention and inclusion of important community leaders such as traditional healers, sports heros, Television celebrities, politicians at national and local level

8.2 Social Mobilisation

 Advocacy of available health services through community health worker (CHWs) structures which is a key component of the Government’s plan to restructure primary care services  CHWs should be involved in door-to-door campaigns, community events, school youth movements, support groups e.g. those undergoing treatment for HIV, TB, faith based organizations and NGOs and CBOs  Health Care Facilities should develop creative and enticing methods of encouraging women to go for screening and include men in their messaging  Health care fora which are established in many communities should we drawn into the campaign and the creative use of drama, poetry, singing and other activities should be used to mobilize the relevant communities.

8.3 User-friendly Health Services

Women friendly services include provision of privacy, clear and comprehensible information, clinics being open at times that working women can access the clinics and methods for women re-entering the clinics for their results should be seamless and without unnecessary attendant bureaucracy.

8.4 CHWs

This policy sees the role of CHWs as central to a successful screening program. CHWs can do the following:  Provide the community (men, women and youngsters) with information on cervical cancer prevention  They can track down women who have abnormal screening tests who need colposcopy  The can support the health care professionals in keeping track of women who either need to be screened or need further diagnostic or therapeutic interventions  They can link their messaging around cervical cancer prevention with other important health care interventions for women over the age of 30 years e.g. o Contraception and the need for dual contraception to prevent the spread of STIs (including HIV) and pregnancy o Breast self examination o Signs and symptoms of other cancers o Signs and symptoms of TB, Malaria o Necessity of booking early for pregnant women o Issues around gender based violence and women’s rights according to various parliamentary acts

9.0 Monitoring and Evaluation

This policy aims to ensure the effective delivery of cervical screening services. An essential part of any screening program is an effective health information system (HIS) that collects basic information to evaluate the success of the program. Managers need accurate and relevant information to determine whether the screening program is achieving its goals of 1] good coverage of the target population 2] using the screening test appropriately and efficiently and most importantly 3] ensuring that women with cervical cancer precursors are identified, and treated.

Appropriate tools must be in place to collect the data required for monitoring and evaluation. These include:  A Pap register to collect data on each Pap smear performed (or whichever screening test is chosen). This is critical at primary facility level  Data collation sheets to summarise Pap register data on a monthly or quarterly basis. Facility managers should use this information to monitor and evaluate at facility level. These data collation sheets should be submitted to district or regional levels for ongoing monitoring and each area should prescribe the appropriate interval for transmission of data  Regular reviews should be conducted to collate screening with treatment and follow-up post treatment. Ideally the NHLS should acquire a computerized system that links screening, with histology and with the cancer registry which is envisioned and has already been gazette.  Data collection and collation should be the responsibility of TRAINED personnel who understand the necessity for accurate, relevant and useable information.  Where facilities either do not provide information or provide inaccurate unusable information, this should be investigated immediately and remedial action taken.  Some of the basic information that facility managers should be collecting include the following: o Proportion of results received by the primary care facility and over what time period o Proportion of results NOT received by the facility and the reason for this o The proportion of women with abnormal smears who receive their results, are referred to the appropriate colposcopy clinic and who ATTEND the colposcopy clinic appointment o The proportion of health care providers at colposcopy clinics who feed back information to the primary care clinic

9.1 Monitoring and evaluation indicators

The following indicators are recommended for monitoring and evaluating the screening program in South Africa and are designed to measure how well the screening program is being implemented.

Indicator Description Source of data Frequency of collation at facility level Screening services Appropriate age for The % of all new smears performed Pap register or Monthly Screening that are on women ≥ 30 years. This cytology measures whether providers doing laboratory Pap smears are adhering to the records national Guidelines regarding screening age group. Coverage The % of target population screened. Pap register Annually This indicator shows how well the programme is doing at screening the target population (all women ≥ 30 who attend public sector facilities). Smear adequacy The % of all smears that are Pap register or Quarterly identified by the laboratory as having cytology endocervical cells. The presence of laboratory endocervical cells, a proxy for records adequacy, is an indicator of the competence of providers in taking Pap smears. Smear abnormality The % of all smears that are Pap register or Quarterly Rate abnormal (by type). This measures cytology trends in abnormal results over time. laboratory records Cytology services Average results turn- Turn-around time, the duration from Pap register Annually around time the date a Pap smear is done to the (special review) date the cytology result is received by the screening facility, indicates how well the system for transporting specimens and results between the screening facility and the laboratory is working, or problems at the laboratory, e.g. staff shortages. Client management at primary care level % clients with This is an indication of how well the Pap register Quarterly abnormal programme is doing at informing Smears informed of women with abnormal smears of their results their results. Colposcopy and treatment services HSIL treatment The % of women with HSIL who are Pap register and Annually Rate treated (it may be within a defined client folders time, e.g. within 6 months of Pap (special review) result). This indicates whether the programme will effectively prevent cervical cancer, as HSIL is the precursor for cervical cancer.

Due to limitations of existing systems for reporting new cases and deaths from cervical cancer, it is not feasible to monitor whether the program is reducing cancer incidence and mortality (impact indicators) at regional, district or provincial levels at this point in time. The National Cancer Registry

28 Draft Ca Cx Policy – September 22nd, 2011 in South Africa collates incidence data for the country as a whole and not by region or province. National Cancer Registry data are therefore useful for evaluating impact at the national level. This is appropriate for South Africa because our biggest priority in the short- to medium-term is to ensure effective program implementation (process indicators are adequate to monitor implementation).

9.2 Using Information to Monitor and Evaluate Cervical Screening Programs

Monitoring and evaluation systems are beneficial only if the information they provide is used by management to improve the co-ordination and performance of the screening program. It is the program manager's role to ensure that the cervical screening information provided by the HIS and supervision systems is utilised for program improvement at various levels. At screening facility level, facility managers may review this information during meetings with staff, at regular intervals. At district and regional levels, appropriate structures that include program managers, HIS task team members and supervisors, should review the information at regular intervals.

9.3 Essential information that managers need to monitor and evaluate cervical screening program include:

 Screening services o Is the appropriate target age group being screened? o Is the program achieving adequate coverage of the target group? o Are staff taking good quality (adequate) Pap smears? o Are staff managing clients with abnormal smears appropriately?  Cytology services o Are cytology results being received by screening facilities? o Is the time period between taking a Pap smear and receiving the result acceptable (< than 6 weeks)? o Are adequacy rates acceptable?  Client management at primary care level o Are clients informed of their screening test results, whether normal or abnormal? o Are clients being managed appropriately according to national guidelines> o Are clients with abnormal smears that need follow-up being identified and traced and referred to the colposcopy clinic?  Colposcopy and treatment services o Are clients with abnormal screening tests being referred as per guidelines? o Are clients attending colposcopy clinics and what proportion of women with HSIL smears are actually receiving treatment and follow-up? o What is the waiting time for women to attend colposcopy clinic (>’r than 3 months is considered too lont) o Are colposcopy clinics feeding back information to the primary health care facility  Impact of the screening service on: o Number of new cases of cervical cancer o Number of deaths due to cervical cancer

o Whether cervical cancer is being diagnosed at an early stage than prior to implementation of the screening program (so-called ‘stage shift’).