Eshetu Lemma Haile

PhD summary

Invasive cervical cancer (ICC) is the fourth most prevalent malignancy and cause of death in women worldwide. It is the second most prevalent malignancy and cause of death among women between 15 and 44 years of age in Ethiopia.  Ethiopia is the second most populated country in Sub-Saharan Africa, with more than 56 million females. It is also one of the least urbanized countries in the world, with only 21.7% of the population living in urban areas.  Ethiopia has 31.5 million women aged 15 years and older and 7,095 women were diagnosed annually with ICC of whom an estimated 4,884 women died from this disease during 2019.  The routine and standard method of cervical cancer screening in Ethiopia is Visual Inspection with Acetic Acid (VIA).  Allthough 20 million women are eligible for cervical screening in Ethiopia, less than 1% of women have been screened.

The first National Cancer Control Plan of Ethiopia (2016 -2020) outlines the dire need for the national implementation of this cancer control plan.  The plan outlines interventions to reduce the burden of cancer through changes in lifestyle, primary prevention, screening and early diagnosis, appropriate follow-up, treatment and provision of palliative care, and advanced stages management, when very little can be done to treat the disease. The low cervical cancer screening uptake is largely due to the low awareness of cancer signs and symptoms, inadequate screening and early detection and treatment services, inadequate diagnostic facilities and poorly structured referral. The country has very few cancer specialists (only 4 qualified oncologists for the entire population). This makes it difficult for a great majority of the population to access cancer treatment services, which results in long waiting times and cause many potentially curable tumors to progress to incurable stages.

The reason for this despondent situation is that the cancer-treatment infrastructure in Ethiopia is inadequate and some cancer-management options are not readily available within the health care system.  Cancer is treated through medical, surgical or radiation therapy, but some patients seek cancer treatment abroad. Effective cancer treatment requires surgical, radiation and chemotherapy be available in the same setting to avoid distant referral and delays in treatment administration. Currently, the Ethiopian essential medicines list does not include chemotherapy for cancer. Even the essential medicines for cancer pain-management are rare to find in most public hospitals.

However, there are opportunities for a program to prevent and control cancer to be developed and expanded in Ethiopia. The country has adopted a comprehensive national action plan on the prevention and control of chronic non-communicable diseases, including cancer. Expansion of cancer treatment services is underway. The country plans a nation-wide scale up of the screening and treatment for cervical pre-cancer into 800 health facilities approximitaley (one health facility per district). The First Lady of Ethiopia guides and leads the cancer-control programme with the Minister of Health, as cancer research in Ethiopia is not proportionate to the magnitude of the problem. This is due to inadequate funding and training facilities in cancer research. There is also no comprehensive cancer surveillance system, and population-based cancer registry limited to the Addis Ababa region at present.

Weaknesses contributing to the poor primary health medical state Ethiopia finds itself in includes low awareness about cancer screening and prevention; inadequate and unskilled staff; lack of pathology laboratories and expertise; the public health service is inadequate and centralized; lack of expertise on cancer diagnosis and treatment as well as lack of diagnostic and treatment facilities.  Public medical service is limited in tertiary hospitals and centralized.  Cancer medicine and supplies are not available and if available it is not affordable.  Minimal palliative care knowledge and practice by health workers, and no palliative-care structure in health care.

The Federal Ministry of Health (FMOH) therefore admits that there is an urgent need to make the most efficient use of the available limited resources for maximum impact, through the identification and implementation of cost-effective strategies and innovations in cancer control.

The cancer control policy notes the possibility of using new technologies, such as HPV DNA testing as well as outreach approaches to reach more women more efficiently to raise awareness of cervical cancer screening.

Other key interventions include:

•  to train health workers on cancer prevention and advocacy
• to utilize opportunities like commemoration days to disseminate cancer prevention information to the community
• to early identify and refer patients suspected of cervical cancer
• to train health professionals on VIA and cryotherapy
• to conduct awareness campaigns
• to provide education and community support materials for patients with cancer
• to improve and increase access to diagnostic and treatment facilities
• to develop action plan for phased introduction of cancer care
• to develop a standard set of equipment required for supplying health facilities with diagnostic equipment
• to train medical doctors and nurses on the chemotherapy protocols identified as standard.
• to develop a staffing plan for optimal use of the radiotherapy unit and develop an education and in/service training plan to implement radiotherapy treatment.
• to improve access to surgery that help diagnose cervical cancer, determine how far the cancer has spread and treat the cancer (especially for early-stage cancers).

The FMOH also commits to develop a health workforce plan for cancer that addresses education as well as in-service capacity building opportunities, harnessing international, regional and national virtual as well as in-person training platforms for different levels of health professionals for cancer diagnosis and treatment.

A publication in January 2021, ' Availability and readiness of cervical cancer screening service at health facilities in Ethiopia' by Tigist Shumet Wasiyhun, et al, Ethiop. J. public health nutr. confirms that cervical cancer is the second prevalent cancer type. It is the most preventable and treatable type of cancer and can be screened and diagnosed early. The need for the availability and readiness of the health facility is inevitable for the provision of these services. This study aimed to assess the availability and readiness of cervical cancer screening service using the Ethiopian health facility surveys conducted in 2016 and 2018.  Data were obtained from Ethiopia service availability and readiness assessment (SARA) 2016 and 2018 which was a national cross-sectional facility-based survey. The availability and readiness of cervical cancer screening service using four tracer items such as; equipment, reagents, training completed and availability of the national cancer prevention and control policies. The results of this study showed:  Nationally, 21% and 33% of the 632 health care facilities included in the study provided cervical cancer screening services in 2016 and 2018, respectively. Among those facilities that provide cervical cancer screening services, 30% of the hospitals and 29% of the health care centers had all tracer items for cervical cancer prevention and control. However, none of the health care clinics had all the tracer items to provide cervical cancer screening services and the service readiness score has remained similar in two periods.

In the conclusion the author states that the overall availability of cervical cancer screening services in health facilities was found lacking; the number of health care facilities rendering cervical cancer screening has increased by 33% in SARA 2018 when compared to SARA 2016, but the level of service readiness remained similar. The author recommends that the FMOH should distribute and ensure constant availability of guidelines, equipment, reagents, and provide refresher training to health care providers.

Although the FMOH did not fare well with the SARA 2016 and 2018 findings, a Press report from the WHO on 5 February 2021 confirms that Ethiopia successfully immunized over 2 million girls against human papillomavirus (HPV) from December 2018 to January 2021. 

The HPV vaccinnation program was introduced in Ethiopia in December 2018, targeting 14-year-old girls. The FMOH lead the rollout and conducted the vaccination in collaboration with regional health bureaus and the education sector, key stakeholders, and different partners including WHO, UNICEF, CHAI, PATH, Jhpiego, Girls Effect and Save the Children. The quadrivalent Gardasil vaccines were acquired through the support of GAVI, the Vaccines Alliance. 

The Human Papillomavirus (HPV) vaccination campaign targeting 2.4 million 14-year-old girls across the country in two cohorts, was completed the end of January 2021. One cohort took HPV – the first dose of the vaccine, while the second cohort was vaccinated the second dose of the vaccine (HPV), which they missed due to school closures in the wake of the COVID-19 pandemic. The vaccination was conducted in schools, communities and health facilities.

Advocacy, social mobilization and awareness creation was conducted in the weeks prior to the vaccination campaign. An expert panel discussion was held at national level, followed by sensitization workshops in five selected regions. Messages were broadcasted on the benefits of the HPV vaccine through national, regional and community media (TV and radio), on educational TV channels as well as in schools to ensure high vaccine uptake.

The WHO provided technical and logistical support to the campaign. WHO central and regional teams provided technical support in monitoring and supportive supervision for quality assurance.

The vaccination of the 2.4 million schoolgirls is a big milestone in the history of cervical cancer screening and prevention in Ethiopia.  Many more similar interventions are desperately required by the FMOH, health care workers as well as the population of Ethiopia.

The prevalence rate of cervical carcinoma as well as abnormal lesions of the cervix are great concerns and must be addressed by all possible means in order to minimize the negative impact of this disease.  The lack of national prevalence statistics is crippling all data related publications.  It is known that the NCR of Ethiopia currently only collates data related to Addis Ababa.  Other data utilized are known from studies done in the various districts of Ethiopia.

Allthough 20 million women are eligible for cervical screening in Ethiopia, less than 1% of women have been screened. The reasons for the low uptake of cervical cancer (CC) screening may also be due to health beliefs and lack of knowledge regarding the primary risk factors causing cervical cancer; the collection method of the cervical samples as well as the distance to travel in order to reach a health facility which provides cervical cancer screening.

The general purpose of this research study is:

• to endeavour to improve the uptake of cervical cancer screening service by evaluating the feasibility of self-sampling as well as HPV testing as alternative screening options in Ethiopia,
• to investigate the cervical cancer screening uptake where women's health beliefs and risk factors lead them to decide whether to be part of the cervical cancer screening program,
• to do a systematic review of the self-sampling HPV detection rate by comparing results from samples collected by clinicians in Africa, and  
• to explore HPV genotype distribution as well as cervical cytology abnormality prevalence rates.

The first research is a cross-sectional study conducted in Adama town, Oromia region, Ethiopia. Women participated voluntarily in cervical cancer screening at St. Aklesia Memorial Hospital. Eighty-three (83) women provided a total of 166 coupled nurse assisted self-samples (NASS) and clinician-collected samples.  Specimens were stored at room temperature and analyzed using the RIATOL qPCR HPV genotyping test.  This is a quantitative Polymerase Chain Reaction (qPCR) high-throughput HPV test utilizing an assay reading the presence of E6 and E7.

The second research study conducted in Adama, Oromia, Ethiopia, involves 412 women participating in this study between September and December 2017.  The purpose of this study was to assess the participating women's health beliefs and risk factors.

The third study is a systematic review and meta-analysis of 250 research articles related to self-sampling HPV testing performed in Africa.  The data was analyzed by comprehensive electronic bibliographic databases of Pubmed, Cochrane, WHO Global health library as well as Popline.

The last study is an institutional-based cross-sectional study with 366 participants. The screening methods were HR HPV DNA testing analyzed using the Abbott Real-Time PCR system and cervical cancer screening performed using conventional PAP cytological techniques.

To summarize the main findings on the first research question (Chapter 2):  Seventy-three women (87.9%) of the participants felt that nurse assisted self-sampling (NASS), using the ThinPrep plastic spatula and endocervical brush rinsed in Preservecyt Solution vial, was comfortable to use.  An overall HPV, HR (High Risk) HPV, and LR (Low Risk) HPV prevalence was 22.7% (15/66), 18.2% (12/66) and 6.1% (4/66) respectively. The overall HR HPV prevalence was 17.2% (NASS) and 15.5% Clinician-taken (CT). The most prevalent HR-HPV type was HPV 51, and the overall measurement agreement between NASS- and clinician-taken samples was moderate with a kappa value of 0.576 (p <0.001).  Women with a history of sexual partners of more than two men showed an HPV result associated with HR HPV positivity (P-value <0.001). There was a significant statistical association between HR HPV positivity and visual inspection with acetic acid (VIA) positive (p value<0.001).

The conclusion of the first research question is that NASS is a good alternative as a sample collection method for HPV testing for cervical cancer screening in Ethiopia.  However, the quality of the collection of the sample does require improvement.  Improved instruction or training of women by the health care workers how to collect adequate samples and to transfer the sample to the Thinprep PreservCyt vial by rinsing the collection device vigourously into the ThinPre PreservCyt may have a definite positive impact on the quality of the sample.  NASS HPV testing may be a valuable tool for the follow-up of women in low-resource setting countries.  Although our study revealed that HPV 51, 31, 16, 45, 52, and HPV 58 was predominantly identified, a large-scale study is required to study the prevalent genotypes in women of Ethiopia in order to aid in the selection of an appropriate HPV vaccine type accordingly. Our research was the first study on HPV detection on NASS using Cytobrush/plastic spatual ThinPrep PreservCyt vial and may be used as a platform for similar studies in the future.  

The second research question (chapter 3) is to evaluate the cervical cancer screening uptake using the health belief model.  Only 6.8% (28/412) women reported that they had visited a health facility (HF) previously for cervical cancer (CC) screening. Among those, thirteen, (3.2% in total) had undergone screening tests either by VIA or Pap test method. More than a third of the women (38.3%) recognized the need to go for regular Pap or VIA tests for early detection of CC.  However, only 11.2% were aware that the first sexual intercourse is associated with increased risk of CC.   Cigarette smoking as an associated factor to intensify the risk of cervical cancer was recognized by 59.2% of the women.

There was a significant association between the educational background of the women and cervical cancer health facility visits (CCHF) (p<0.05). Women who had a family history of CC, showed an increase interest to visit the CCHF for check-up purposes (p<0.05). Eligible women did not feel threatened by the risk of developing cervical cancer. Only 41.5% of women partaking in this study, indicated that they knew the benefits of cervical cancer screening.

In this study, women believe that the main barrier factors for not visiting clinics for screening were because they douche vagina daily (p <0.05) and no “screen-and-treat” approach (STA) cervical cancer screening modalities was available at the health care facilities (p<0.005).  The women who visited clinics for CC screening were statistically associated with when they had symptoms, sex with many partners as well as those women taking contraceptive drugs or contraceptive devices (p<0.05).

The health beliefs model used to explore the reasons for the Ethiopian women’s lack of participation in cervical cancer screening as well as the factors for prevention of CC, and so on, may assist with the design of culturally appropriate cervical cancer screening interventions. Therefore, addressing issues of low screening uptake and visiting health clinics might require more than one theory, considering there may be no single theory suitable for all cases. Hence, further study is required to explore other possible factors contributing to low screening uptake and clinic visits for cervical cancer screening.

A systematic review of African studies conducted to explore self-sampling HPV detection rate and its acceptability compared with that collected by doctors (Chapter 4).  Eight research articles from six countries in the African continent with a total of 3,476 women included in these studies, formed part of the systemic review.  On average the high risk (HR)-HPV detection rate was 36% (7.2 -84.8%) and 35% (6.8 - 87.8%) for self- and clinician-collected sampling, respectively. The average differences and variation of HPV rates between sampling methods were 2.6% (SD =1.7). There was correlation (r=0.997) between the HR-HPV detection of the two sampling methods. The moderate kappa agreement 0.71(0.47 to 0.89) between the two sampling techniques was found.

In general, women concluded that the self-collected sampling method was the preferred method of sample collectiom (86.3%) and easy to obtain (77.8%).  The acceptability of self-collected HPV testing could be an alternative sampling method that provides equivalent and comparable HPV detection to that of clinician sampling methods and may therefore increase the uptake of screening services. Introducing standardized self-sampling and a diagnostic assay across African countries may be very useful for strengthening the cervical cancer screening strategy.

As this review study only focused on African-based studies, there are several concerns regarding the full introduction of self-sampling into the African health care systems. Most African countries still use conventional PAP smear and VIA for cervical cancer screening programs due to the relatively low cost; however, skilled and trained nurses, doctors and pathologists are required for the least developed countries where these skills are extremely scarce. Thus, to introduce HPV tests using self-collected sampling, some level of infrastructure with relevant equipment, reagents, electricticity as well as a skilled workforce are required.

The fourth study aimed to assess the burden and genotype distribution of high-risk human papillomavirus (HR HPV) infection and cervical cytology abnormalities at selected obstetrics and gynecology clinics of Addis Ababa, Ethiopia (chapter 5). The overall HR HPV burden of 13.7% and the abnormal cytology prevalence rate of 13.1% respectively were confirmed. The majority of HR HPV types were other than types 16 and 18. Of the total abnormal cytology results, 81.3% of the smears collected were diagnosed as low-grade squamous intraepithelial lesions (LSIL), 12.5% and 6.3% of the smears collected were diagnosed as atypical squamous cells of undetermined significance (ASCUS) and high-grade squamous intraepithelial lesions (HSIL), respectively. The HR HPV infection rate correlated well with the geographical area of residence of the patient, her occupation as well as her HIV serostatus.  Other associated factors include the age of the patient, her age at first marriage as well as her education level.  The overall agreement between Abbott Real-Time HR HPV DNA PCR results as well as Pap smear cytology screening results was 78.96% (Kappa value of 0.12, 95% CI (0.00–0.243), P=0.01).

Non-16/18 HR HPV genotypes represented the largest proportion of HR HPV infections in this study. Women without cervical cytology abnormalities had the highest frequency of HR HPV infection.  This may be due to high sensitivity rate of the assay, Abbott Real-Time HR HPV DNA PCR, utilized in our study. The burden of HR HPV infection and cervical cytology abnormalities presented in this study are consistent with the few previous local studies and reviews done in Ethiopia, yet somehow lower than the estimated prevalence for sub-Saharan Africa.

The performance of the Abbott Real-Time HR HPV DNA PCR and Pap smear cytology screening methods require further evaluation using histology as the gold standard. A large-scale community-based cohort study is recommended in order to determine the national burden of HPV and cervical cytology abnormalities.  The outcome of this large study must be designed to recommend the ideal screening algorithm in the local context and therefore will significantly contribute to the national preventative public health strategies against cervical cancer.

The last chapter is (chapter 6) is summarizing and discussing the overall findings of our studies. Accordingly, nurse assisted self-sampling could be used as an alternative sample collection method for HPV primary screening testing in Ethiopia particularly for the remote rural population areas since comparable results and moderate agreement between doctors versus self-sampling was found.  However, the quality of the sample requires improvement by intensifying training of all relevant health workers on the proper collection of an endocervical sample and then transferring the sample to the vial by rinsing the collection device vigourously in the ThinPre PreservCyt vials. The HPV detection variation between the two sampling methods are expected due to, as noted in different research studies, sample collection steps, sample collection devices, the use of different HPV detection assays, and geographical location of the patient. For example, the overall HPV prevalence rate in our two studies, capital city (Addis Ababa) versus special zone of Oromia (Adama) town geographical area, was 13.7% and 22.7%, respectively.

Our study may show that screening uptake can be increased with the implementation of NASS and/or clinician collected samples for HPV testing. It is recommended that the government should design a cervical cancer screening model that reduce the number of follow-up clinic visits for women by implementing one-stop first visit STA health facilities customized for the Ethiopian health care system.

Even if HPV testing is resource-dependent, HPV testing is recommended above VIA.  HPV testing should be provided where it is affordable, implementable and sustainable over time. This recommendation applies to women regardless of HIV and any other sexually transmitted disease status. Although recent cluster randomized trial study in Ethiopia revealed that self HPV testing significantly improved uptake over VIA, the authors recommended that the FMOH of Ethiopia may design a longitudinal comparative large scare study of HPV testing and VIA testing to determine variations in specificity, sensitivity, screening uptake, adherence to procedures, feasibility and cost-effectiveness and algorithim design.

 Appropriate awareness and education of women when visiting the health facility have a significant positive impact on the outcome of low screening uptake. Timeous testing and confirmation of the HPV genotypes in the country is necessary.  This information will advise the suitable HPV vaccines to be utilized in the future for national vaccination programs. Our study identified a wide range of genotypes and prevalence rates of HR HPV.  

We assessed women's perception or health beliefs and risk factors towards cervical cancer disease and screening participation.  Most women confirmed that they never visited health clinics for cervical cancer screening mainly due to misperception, e.g. assuming regular vagina douching prevents gynaecological challenges.  Cultural and religious beliefs, fear of their husband’s decision to agree with cervical examination, limited knowledge on risk factors, unawareness of which health facility provides the service, long waiting time, shortage of finance, etc. were added factors contributing for low visit of health clinics for purpose of cervical cancer screening. Most women visit clinics at the late stage of disease as to avoid repeated clinic visits and follow ups.

Designing culturally appropriate cervical cancer screening interventions through scientific studies of women's perception in detail is crucial. Therefore, addressing issues of low uptake of CC screening or health clinic visits may require more than one theory, since there may be no single theory that is suitable for all cases. Hence, a supplementary study is required to explore other possible factors contributing to the low uptake of clinic visits and screening for cervical cancer.