Advancing the elimination of cervical cancer across Africa

Domain: biology
Published: 2026-03-13
Editorial outcome: minor_revision

Abstract
Though cervical cancer is largely preventable, Africa faces a high burden with thousands of deaths. Highlighting the urgent need for action toward the WHO's 90-70-90 elimination strategy, this study presents the epidemiological burden of HPV and cervical cancer in Africa and advocates for decisive measures to improve screening and implement effective prevention through vaccination. Here, we discuss which is the better option for Africa: a single-dose or a two-dose vaccine regimen. Furthermore, we explore screening methods, such as methylation markers and AI-based screening, as well as treatment-related side effects and the prognosis of cervical cancer in Africa.

Introduction
Cervical cancer remains a global public health concern. With millions of cases around the globe, the World Health Organization (WHO) has called for the elimination of cervical cancer as it is an almost entirely preventable disease by effective primary (prophylactic vaccines), secondary (screening), and tertiary (early treatment) prevention measures1.

WHO developed the 90-70-90 strategy, which aims to (1) vaccinate 90% of girls with the HPV vaccine by age 15, (2) screen 70% of women by age 35 and again at 45 with a high-performance test, and (3) treat or manage 90% of diagnosed women1. Many developed countries have committed to achieving the 90-70-90 strategy, with countries such as the U.K., the USA, and European countries implementing widespread HPV vaccination and screening programs2. For example, Australia, the first country to initiate nationwide HPV vaccination, experienced a decline in high-grade cervical abnormalities after vaccination, halving from 2007 to reach 5.0 per 1,000 screened nationally by 2014 in women aged less than 203. Also, a mathematical model estimated a reduction to six cases of cervical cancer per 100,000 by 2020 and a further decrease to four cases per 100,000 by 2028 in Australia4. In the U.K., a substantial reduction in cervical cancer (87%) and high-grade cervical abnormalities (97%) was observed after vaccination of women who were aged 12-13 during the period of immunization5. However, across low- and middle-income countries (LMICs), this remains a reality yet to be achieved. A mathematical model suggests that if LMICs attain the 90-70-90 strategy goal by 2030, the incidence of cervical cancer could fall by 42%, with over 62 million cases averted by 21206.

In this review, we aim to promote a deeper understanding and encourage prompt, decisive action to eliminate cervical cancer as a public health issue in Africa and to shed light on the current outlook for HPV and cervical cancer on the continent. We highlight epidemiology, prevention, screening, treatment, and prognosis.

Results
2. Epidemiology
2.1 Cervical Cancer in Africa: A Public Health Concern
Globally, an estimated 660,000 new cases of cervical cancer and 350,000 deaths occurred in 2022, with 125,699 new cases and 80,614 deaths in Africa1,7. Cervical cancer has long been under-prioritized in developing countries, especially in Africa8. The highest age-standardized incidence rates were observed in Eastern Africa (40 [95% CI = 39.7–40.4]), followed by Southern Africa (36.4 [95% CI = 35.8–37.1]), and Central Africa (31.6 [95% CI = 31.1–32.1]). Mortality rates followed a similar pattern to incidence, with the highest recorded in Eastern Africa (28.6 [95% CI = 28.3–28.9])9. HPV infection and cervical cancer have become particularly worrying in terms of socio-demographic, economic, and health conditions. Campos et al. studied cervical cancer prevention in 50 LMICs. They discovered that implementing HPV vaccination and once-in-a-lifetime screening could prevent 5.2 million cases, 3.7 million deaths, and 22.0 million disability-adjusted life years (DALYs) over the lifetimes of the intervention cohorts. The total cost of the 10-year vaccination, screening, and treatment program was $3.2 billion, deemed cost-effective10.

2.2 HPV Prevalence and Genotype Distribution
The prevalence and genotype distribution of HPV vary by geographic region, age, and HIV burden. Understanding the epidemiology of HPV in Africa is critical in developing a prophylactic HPV vaccination strategy and estimating the impact and resource planning for HPV screening, triage, and precancer treatment. In a five-continent meta-analysis among women with normal cytology, HPV prevalence ranged widely: 24% in sub-Saharan Africa, 21.4% in Eastern Europe, 16.1% in Latin America, 9% in Asia, and 5% in North America11; the highest prevalence was observed in studies conducted in Southern African countries. In the rural Eastern Cape Province of South Africa, the overall HPV prevalence in sexually experienced girls aged 15-22 was 76%, and the prevalence of carcinogenic HPV was 54.5%12. Also, HPV is among the most common sexually transmitted diseases in North Africa, with a prevalence of 23%13. In a meta-analysis covering the Middle East and North Africa (MENA), the study reported that the subgroup with abnormal cervical cytology in the MENA region with the highest HPV prevalence was found in Northeast Africa (94%; 95% CI = 91–96%), which was the same in the general population subgroup in the region (21%; 95% CI = 7–40%)14.

Beyond overall prevalence, the distribution of specific HPV genotypes also exhibits distinct regional patterns. The five most common HPV types reported worldwide among women are HPV-16, -18, -52, -31, and -5815. Sub-Saharan African (SSA) trends diverge from these global averages; while HPV-16 and HPV-52 are the primary genotypes in Eastern and Southern Africa, HPV-16 and HPV-35 are the predominant genotypes in Western Africa16-18. In contrast to SSA, the most detected HPV types in the MENA region align more closely with global reports (HPV-16, -18, and -58)14.

The prominence of genotypes like HPV-35 highlights a growing concern about Non-Vaccine-Targeted (NVT) carcinogenic genotypes (including HPV-39, -51, -56, -66, and -68) in Africa. HPV-35 is only associated with about 2% of global cervical cancer cases; however, in Africa, it occurs in about 10% of precancerous and cervical cancer cases19. An Ethiopian study showed that the prevalence of NVT HPV was 56 of 108 women (51.8%, 95% CI = 42–61%), of whom 28 (25.4%, 95% CI = 18–34%) had a single NVT HPV genotype infection. Also, HPV-35 accounted for the highest prevalence of NVT HPV cases (11 cases)20. Another study involving Kenyan and South African women showed that HPV-35 (8.4%) was as prevalent as HPV-18 (8.4%). In this study, a few (1.9%) had evidence of high-grade cervical abnormalities, among which HPV-35 was the most prevalent21.

While demographic, socioeconomic, and lifestyle factors, geographic variations, and existing STI infections primarily influence HPV prevalence80,81, it is crucial to acknowledge that methodological factors in HPV testing also contribute to variations in reported prevalence. For instance, a Malawian study observed differing prevalence rates when using the Xpert HPV test (Cepheid, USA) versus ScreenFire (Atila Biosystems) on the same population, reporting 100% and 90% prevalence, respectively. This may have resulted from storing specimens for 1 to 2 years before testing with ScreenFire49.

2.3 The interplay of HIV and HPV
SSA has the highest cervical cancer rate worldwide. These rates are worsened by factors such as the high HIV prevalence, a high rate of unprotected sex, sexually transmitted infections, and insufficient sexual and reproductive health education among young girls and women82. Both HPV and HIV infections share the same transmission route, and cervical cancer has been considered an AIDS-related disease since 1993. HIV infection is associated with an increased risk of acquiring new HPV infections and a reduction in the rate of HPV clearance83.

The high burden of HPV among women living with HIV (WLWH) in Africa has significant implications for cervical cancer prevention, as the prevalence of single or multiple HPV infections is higher among WLWH 84. This increased risk is further worsened by factors such as HIV viral load, as Akakpo and colleagues showed that WLWH with viral load ≥ 1000copies/ml (AOR = 5.58, 95% CI = 2.89-10.78, p < 0.001) had a higher likelihood of being co-infected with HIV and HPV85. Beyond the general prevalence, the most frequent carcinogenic HPV types among African WLWH were HPV 16 (18%), HPV 35 (10.12%), HPV 52 (9.98%), HPV 18 (9.7%), and HPV 45 (6.82%)86. Another study across three SSA countries demonstrated that the prevalence of single and multiple HPV infections, HPV 16, -18, -35, and -45, was higher and more common among WLWH than among HIV-negative women87. Although HPV 16 was the most frequently observed genotype, the significant prevalence of non-vaccine HPV 35 is evident. A recent study from the extensive African Cohort Study, which involved 12 clinics across Tanzania, Kenya, Uganda, and Nigeria, found a significant prevalence of HPV 35 at 9.3%19. Moreover, in 2022, a comparative study by Gilles et al. (2022) involving WLWH and HIV-negative controls specifically highlighted HPV 31, 33, and HPV 35 as more prevalent in WLWH88. This consistent and high prevalence of HPV-35 across multiple African settings, particularly among WLWH, shows a critical gap in the current vaccines available, which do not include this genotype. This justifies prioritizing its inclusion in future vaccine development or regional vaccination plans.

3. HPV Vaccination and the African Context
HPV vaccination is an essential preventive method for cervical cancer89. Boily et al. conducted a mathematical modeling study and found that implementing a program in which girls receive the HPV vaccine and participate in lifetime cervical cancer screenings could eliminate cervical cancer in the South African region by the end of this century90. 28 of 47 SSA countries have integrated HPV vaccination into their national routine immunization programs, with four countries reaching 90% HPV vaccination coverage in 2023. Also, 17 SSA countries have incorporated HPV testing into cervical cancer screening programs91,92. Most of these countries are supported by the GAVI Alliance, a funding scheme aimed at achieving global vaccination equity93. However, not all GAVI-funded nations have incorporated vaccinations at the national level.

Currently, six preventive HPV vaccines (Cervarix ®, Cecolin ®, Walrinvax ®, Cervavac ®, Gardasil ®, and Gardasil 9 ®) are licensed and widely recognized97. Girls aged 9-14 are recommended to receive the HPV vaccination as early as possible before their sexual debut1. Additionally, some middle- and high-income countries have implemented the "gender-neutral" vaccination program recommendation to immunize both boys and girls98. Due to resource limitations, only Cameroon, Cape Verde, and Mauritius have implemented "gender-neutral" vaccination programs92.

In Africa, the HPV vaccination program mainly targets girls aged 9-14 through school-based HPV vaccination, which is integrated into school routine programs for adolescents99. This can be integrated with adolescent health services100, as seen in Tanzania’s HPV-Plus program, which provided additional services, including health education, deworming tablets, nutritional assessments, and visio screening101. However, school-based vaccination requires extra resources and costs, potentially limiting other school activities102. In addition to focusing on adolescents, a study suggests that combining cervical cancer screening for mothers with their daughters' HPV vaccination (Mother-to-daughter vaccination) in a single program can further enhance maternal knowledge of cervical cancer103.

Furthermore, some countries have implemented community-based routine immunizations in which vaccines are delivered via mobile clinics, door-to-door campaigns, or community health workers. This strategy helps provide healthcare services to out-of-school girls and the community, including vaccinations at health facilities104,105. Some countries, such as Nigeria, use a mixed approach that combines school- and community-based vaccination strategies93.

3.1 Efficacy and shortcomings of vaccination programs in Africa
There is substantial evidence supporting the effectiveness and safety of HPV vaccines106,107. As the first African country to implement an HPV vaccination program, Rwanda introduced a quadrivalent vaccine for girls aged under 15. This significantly reduced the prevalence of HPV types 6, 11, 16, and 18108. Moreover, a survey in Rwanda and Bhutan found that administering the quadrivalent vaccine in these regions provided cross-protection against five additional HPV types (HPV 31, 33, 35, 52, and 58)109. To offer faster herd immunity, HPV vaccination programs implemented in Africa typically follow a two-dose schedule. Although this improves cost-effectiveness, HPV vaccination rates in many African countries remain below WHO targets110.

As a developing region, low vaccination rates are influenced by systemic barriers such as a lack of political will, limited vaccine supply, high costs, and scarce healthcare resources. Educational policies also pose challenges; in countries where compulsory education ends at primary school, ensuring full vaccination coverage may be particularly difficult for out-of-school or transferred children111. To improve coverage, support from national authorities and coordination among schools, communities, healthcare providers, and health ministries are essential112.

Moreover, individual factors also play a role. In Uganda, financial constraints and a lack of education about HPV affected vaccination uptake113. Similarly, limited access to information has been cited as a barrier in North Africa114,115. Other personal factors include religious beliefs, fears of infertility or side effects, misinformation online, mistrust of healthcare systems, and attitudes of healthcare workers116,117. The COVID-19 pandemic further hampered vaccination efforts, as misinformation about the safety of COVID-19 vaccines increased vaccine hesitancy, delaying or preventing HPV vaccination even when services were available104.

To address these challenges, Okunade et al. and Fokom Domgue et al. suggested adopting mobile health technologies or promoting communication between people and their communities to increase awareness of the HPV vaccine and reduce vaccine hesitancy, thereby improving HPV vaccination rates118,119. Furthermore, strengthening HPV vaccination programs is particularly crucial in countries with a high HIV burden, where WLWH face elevated risks. However, reports on the specific effects of HPV vaccination in this population remain limited120.

Data from other countries suggests that a reduced-dose vaccination schedule may help prevent persistent HPV infection, lower costs, simplify vaccination processes, and increase coverage121-123. Specifically, two studies from Tanzania demonstrated that a single dose of the Cervarix® or Gardasil 9® HPV vaccine was well tolerated in healthy African girls aged 9-14124,125. Following WHO recommendations, 16 African countries are considering implementing a single-dose HPV vaccination program92. However, there are limited follow-up periods (approximately 24-36 months) in two key single-dose vaccine trials in Africa (KEN SHE and DoRIS), and the long-term protection over 10 years has not been validated126. Existing studies primarily assess the protective effect based on immunogenicity data rather than clinical endpoints, such as cervical cancer incidence.

Additionally, there is a large population of WLWH in Africa. Studies on the single-dose HPV vaccine for immunocompromised girls are limited126. Although a study in South Africa evaluated the impact of the single-dose vaccine on HIV-infected girls, concluding with a reduction in post-vaccine HPV 16/18, it has limitations, as it did not imitate all WLWH in Africa127. Currently, there are no large-scale, long-term prospective studies evaluating the protective effect of the single-dose HPV vaccine in HIV or HPV-infected populations.

Conversely, a mathematical modeling analysis indicated that an extended-duration two-dose HPV vaccination schedule might be easier to implement than a one-dose schedule, for which the ultimate protective efficacy remains uncertain. It may be more effective than the current two-dose schedule and can help prevent interruptions to vaccination programs128. For instance, during humanitarian crises, some refugees or nomadic groups may be forced to live a constantly mobile, transnational lifestyle, often lacking access to adequate medical personnel and vaccine supplies129. Additionally, severe infectious disease outbreaks, such as COVID-19, increased demand for healthcare workers and caused shortages of medical resources, potentially delaying or interrupting HPV vaccination programs during such emergencies130,131. In such situations, a two-dose HPV vaccination program with an extended schedule may be easier to implement than the current two-dose approach. Reduced-dose and extended-duration two-dose HPV vaccination schedules may become key preventive measures to significantly reduce cervical cancer incidence in LMICs in the future.

4. Cervical cancer screening
Persistent HPV infections, especially carcinogenic HPV types 16, 18, and 45, are the leading cause of cervical cancer globally. However, persistent infections last for many years before leading to abnormalities132. The time gap between infection and disease onset provides an opportunity for early detection and intervention, thereby potentially reducing the incidence and mortality of cervical cancer.

Screening is crucial as a secondary prevention measure in addition to increasing vaccination coverage. The main objective of cervical cancer screening is to identify treatable precancers that are likely to develop into invasive cancers. This proactive approach aids in reducing the incidence, mortality, and morbidity associated with cervical cancer. A secondary but important goal is the detection of early-stage cervical cancer, which helps with early treatment, hence reducing the mortality of cervical cancer133. Cytologic testing, including Pap testing and, more recently, liquid-based cytology, has served as the basis for primary cervical screening methods, effectively detecting cervical abnormalities in many developed countries over the years. Visual Inspection with Acetic Acid (VIA) and Lugol’s Iodine (VILI) are also used for screening133,134.

However, recognizing that carcinogenic (high-risk) HPV is the cause of cervical cancer is essential for screening. According to the WHO guidelines, women should be screened for cervical cancer every 5–10 years starting at age 30. WLWH should be screened every 3 years starting at age 25. The global strategy encourages at least 2 lifetime screens with a high-performance HPV test by age 35 and again by age 451.

HPV testing identifies the presence of carcinogenic HPV DNA in vaginal and cervical samples. WHO recommends primary HPV DNA testing and triage for women living with HIV, while suggesting optional triage for the general population135. Most HPV DNA assays are integrated with partial genotyping, which identifies the carcinogenic HPV types, mainly HPV 16 and 18, or extended genotyping, which detects a broader range of carcinogenic HPV types, enabling better risk stratification136. Women who are suspected to be at higher risk for cervical cancer are advised to undergo triage using either HPV genotyping or cytology.

WHO has set two screening approaches: "screen and treat” and “screen, triage and treat”137. In the “screen-and-treat approach,” the treatment decision is based solely on a positive primary screening test, without a secondary test. A “visual assessment for treatment (VAT)” is performed after positive primary results using visual inspection to determine eligibility for ablative treatment138. When the patient is eligible for ablative treatment, it is ideally done immediately, at the same visit as the screening test (the single-visit approach)137. Whereas in the “screen, triage, and treat approach,” the decision to treat is based on a positive primary screening test followed by a positive second test (a “triage” test). Also, a positive triage test may lead to biopsy and histopathological examination to diagnose and determine appropriate treatment. When the primary screening test is positive, and the triage test is negative, women need an appropriate follow-up evaluation at a specified date, according to the recommendations137.

Africa, comprising numerous LMICs, faces resource constraints compared to developed countries or fast-growing economies. Due to these constraints, VIA or VILI is often used as the primary cervical cancer screening as it is a low-cost procedure139. A nine-year study in Zambia demonstrated the practical use and outcomes of VIA, tracking cervical cancer screening outcomes through Visual Inspection with Acetic acid and digital cervicography (VIAC)140. The study involved over 180,000 women and showed a 10.4% VIA positivity rate, with WLWH aged 30-39 exhibiting the highest rate. However, follow-up rates declined over time140. While VIA remains essential in resource-limited settings, it has limitations compared to advancements like HPV testing. For instance, a study in Eswatini with over 600 women supplemented VIA with HPV testing, which increased detection accuracy by identifying 223 women who tested negative on VIA but positive for HPV34. This shows that women unaware of their HPV status are at risk of late diagnosis if relying solely on VIA.

4.1 Enhanced Visual Assessment and the Potential Role of Artificial Intelligence in Screening
Technological advancements, such as computer-aided (smartphone-aided) methods and artificial intelligence (AI), are increasingly being integrated into VIA protocols in African countries141. A study in Eswatini confirmed a significant improvement in VIA using smartphone-aided screening, demonstrating greater diagnostic consistency than traditional VIA142. Benefits include easier consultations among healthcare workers, better communication with patients, high-quality image assessment, and increased efficiency, reducing workload143,144. However, successful implementation requires proper technology management, including regulations, infrastructure, and training. Involving patients in the process can also help ensure these tools are widely adopted and effectively integrated into screening programs144.

AI has the potential to significantly improve cervical cancer screening in Africa. Since 2017, the Enhanced Visual Assessment (EVA), a clip-on attachment for Android phones that functions as a mobile colposcope with integrated AI software, has been considered for use145. This AI, a Convolutional Neural Network (a type of machine learning) trained on over 100,000 cervical images from the U.S. National Cancer Institute, helps identify precancerous and cancerous lesions. Studies show that Automated Visual Evaluation (AVE) using EVA can accurately detect high-risk lesions, demonstrating strong correlation with expert evaluation146, with one study in Zambia reporting sensitivities of 85% and specificities of 86%147. A recent prospective study evaluating the performance of the AVE tool for screening across five African countries found that AVE significantly outperformed VIA in sensitivity for detecting high-grade lesions, demonstrating its potential to improve screening effectiveness in resource-limited settings148.

Beyond visual inspection, AI is also transforming cytology analysis. In rural Kenya, a trial with 740 HIV-positive women digitized cervical smear samples using a portable scanner, which were analyzed by a deep learning system (DLS) trained on over 350 images and validated on 361 images149. The system demonstrated high sensitivity (95.7% to 100%) and reasonable specificity (78.4% to 84.7%). Notably, the DLS accurately identified high-grade lesions and had no false negatives in cases rated high-grade by manual reading149. This shows AI's potential to enable early detection and improve cervical cancer screening in resource-limited settings.

4.2 Performance and Feasibility of Various Cervical Screening Methods
Vassilakos et al. conducted a Test-Triage-Treat (3T) study in Cameroon to compare the performance of commonly used screening methods. Women initially underwent HPV testing, with those testing positive subsequently proceeding to VIA and cytology examination (manual and automated). The sensitivity of single-test automated cytology was higher than that of the other systems (manual cytology and VIA). However, combining HPV-16/HPV-18/45 genotyping and automated cytology yielded the highest sensitivity for CIN 2+ detection (91.2%, 95% CI = 74.8-97.3%)28. Another study in South Africa confirmed that a combination of HPV tests and other screening methods was the most effective in detecting cervical intraepithelial lesions. In this study, VIA performed poorly and did not meet the set standards. However, hrHPV testing was the most sensitive, while cytology showed the greatest specificity. The dual combination of hrHPV (HPV 16/18 genotyping) and cytology for ASCUS+ had the highest sensitivity amongst others. The study confirms that using hrHPV testing as the primary test with others (HPV-16/-18, cytology, and VIA) as the secondary test is the best strategy for screening in HIV-positive or HIV-negative people64. Furthermore, a similar study in Burkina Faso and South Africa also confirmed that hrHPV testing is more sensitive for CIN2+ detection, and triage of HPV-positive patients with cytology had optimal specificity, although with a slight loss in sensitivity26. Therefore, combining HPV tests and other screening methods may benefit low-resource countries.

Furthermore, adjusting the cut-off values for the cycle threshold (Ct) in HPV genotyping assays may enhance specificity while causing minimal sensitivity losses. The cycle threshold for HPV channels effectively predicted CIN2+, as Kuhn and colleagues showed150.

In recent years, alternative methods have been employed for cervical cancer screening in South Africa. Analysis of hypermethylation in specific host cell gene promoter regions is an increasingly intriguing method for identifying women at high risk of cervical cancer or advanced CIN lesions, as reported in recent studies151-157. One study aimed to validate the methylation markers ASCL1 and LHX8, identified in a genome-wide DNA methylation profiling study158 as the primary screening method. The findings indicated that the sensitivity and specificity of ASCL1 and LHX8 as single markers were similar to those of HPV testing. However, combining both markers resulted in decreased sensitivity for CIN 3 detection but increased specificity compared to primary HPV testing without losing sensitivity. They suggested these combined markers might be better than primary HPV testing, potentially reducing referral rates and overtreatment66. Another study also used ASCL1 and LHX8 methylation analyses as post-treatment monitoring markers for women treated for CIN 2/3. The study demonstrated that the ASCL1/LHX8 methylation test is associated with a low risk of recurrent CIN 2/3 after LLETZ (LEEP) treatment among test-negative individuals, while maintaining a high detection rate of recurrent CIN 2/3159. These studies emphasize methylation markers as a promising approach, providing potential for more precise cervical cancer screening and post-treatment monitoring.

Although several screening methods have been explored for use in Africa, their feasibility varies depending on factors such as cost and infrastructure. Visual Inspection with Acetic Acid (VIA) is inexpensive and requires minimal resources, but it has the lowest sensitivity for detecting dysplasia160,161. WHO recommends HPV DNA testing due to its higher sensitivity for detecting carcinogenic HPV. Although initially costly, recent studies show HPV testing is more effective and cost-efficient in the long run, especially when combined with single-visit "screen-and-treat" strategies138,160,162-164. Using existing nucleic acid testing platforms, such as Xpert HPV (Cepheid, USA) and AmpFire (Atila Biosystems), has further reduced costs and improved scalability163. Scaling up these methods could significantly enhance cervical cancer screening across Africa, provided a reliable supply of test cartridges is maintained165.

Scaling up cytology-based screening in Africa is less likely to be practical. It is relatively costly and needs specialized infrastructure160,161. Additionally, methylation markers require expertise and specialized techniques, which can be difficult in low-resource settings151-157. Therefore, policies should evaluate the cost-effectiveness of methods and identify infrastructure gaps and other factors during decision-making for national screening programs.

5. Cervical Screening Coverage Rates in Africa
Cervical cancer is usually diagnosed in advanced disease stages among women in Africa166-169. A meta-analysis on survival revealed that 53.3% (95% CI = 50.9-55.6%) of cervical cancer cases in Africa were diagnosed at late stages (stage III-IV). This proportion varied significantly across countries and regions, ranging from 7.7% to 86.3%. Considering only SSA countries, the study showed that 56.3% (95% CI = 53.7-58.8%) of cervical cancer cases were presented in the late stages (stages III-IV)170.

The observed high rates of late-stage diagnosis are directly related to persistently low cervical cancer screening coverage across Africa166-169. Screening coverage rates in Africa remain very low, ranging from 2% to 20.2% in urban areas and from 0.4% to 14% in rural regions171, with an overall screening prevalence of merely 10%172. Examining trends in cervical cancer screening from 2000 to 2020, only Southern Africa experienced an increase in screening coverage among women aged 30-49, while Eastern Africa showed a slight rise, and Western and Central Africa showed slight declines173. Hailegebireal et al. and Yang et al. both highlighted Benin’s low lifetime screening rates, with only 1% of women aged 30-49 screened, the lowest, while the highest proportion of women screened in a lifetime was in South Africa and Namibia172,173.

Low screening rates and late-stage diagnoses across Africa stem from various barriers at individual, community, and systemic levels. At the individual level, factors such as rural residence, low education, and financial challenges limit access to care. Many women delay seeking healthcare due to a lack of awareness about cervical cancer, its symptoms, and the importance of early screening166-169. Notably, one study reported that HIV-negative women did not recognize the need to seek healthcare, which emphasizes the lack of awareness167. Furthermore, socio-cultural factors such as religious beliefs and negative partner involvement can deter women from accessing screening services174. Within healthcare systems, barriers include overburdened facilities, insufficient equipment, and staff shortages175. Healthcare providers may have limited knowledge of cervical cancer signs and hold negative attitudes toward screening167-169,175, with some displaying implicit biases—nurses show the highest levels of bias176. Misconceptions among providers and policymakers about the acceptance of screening programs further hinder coverage174,175. Addressing these barriers could improve screening rates.

Self-sampling for primary HPV testing has increased screening coverage, with high acceptability shown in studies177-179, including a systematic review across eight LMICs, mainly in Africa, where acceptability was 92.6%, even among WLWH (87-100%)180. A study on Catholic nuns in Ghana suggests that women with religious beliefs may prefer self-sampling, as it aligns with their privacy and beliefs181. Benefits include comfort, autonomy, and reduced fear of pain, while drawbacks include anxiety over sample quality181-183. The accuracy of self-sampled HPV tests compared to clinician-sampled HPV tests shows that the sensitivities and specificities of HPV testing for the CIN2+ and CIN3+ endpoints did not differ between the two, confirming that self-sampling could be used for primary HPV screening184. The performance of self-sampling and clinician sampling was comparable across studies from Africa (concordance rates ranged from 79.7% to 94.2%)180.

Self-sampling can help overcome some barriers to screening. Still, personal issues (such as lack of knowledge, fear, doubts about accuracy, and cost), environmental factors (such as discrimination and transportation), and structural problems (such as high costs, limited resources, and poor access) may limit its use180. Governments should incorporate self-sampling in national programs and work with agencies, donors, and NGOs to make kits more affordable and available. Increasing health insurance coverage for these kits could also boost participation. Expanding outreach through mobile clinics and community health centers, and mailing kits with phone support for results, can further reduce barriers180.

5.1 Strengthening Screening Coverage, Capacity, and Sustainability
Evidence-based implementation approaches should be used to design and deliver patient awareness and education programs to enhance patient engagement and address issues such as treatment nonadherence, vaccine hesitancy, and refusal to be screened185. Additionally, educating healthcare professionals through training and hiring more lab workers is crucial to increasing in-country capacity and improving awareness186,187. Developing culturally relevant cervical cancer education intervention for women and healthcare providers in LMICs could be an effective strategy to reduce bias176,188. To further address patient disengagement, improve adherence, and overcome hesitancy, training on emotional intelligence, counseling, and effective communication between patients and healthcare providers may positively influence behaviors and outcomes188,189.

The use of mobile health (mHealth) in oncology education and tele-mentoring can effectively enhance cancer screening knowledge among healthcare providers, as mobile technology is widely accessible and cost-efficient190-192. However, supervision and face-to-face interactions should be conducted in conjunction with mHealth services to ensure effectiveness. Training initiatives should prioritize developing competencies through sustained mentorship and supervision rather than relying solely on short-term lectures193,194. While support from international organizations may be crucial initially, reliance on external funding should decrease over time as local capacity becomes sufficient. Providing funding for healthcare workers to pursue further studies can improve faculty retention, and local governments should take responsibility for maintaining these efforts, ensuring a long-term plan for recruiting and fairly compensating newly trained health professionals193. The C4P costing tool, developed by WHO, can assist national cervical cancer programs in estimating the financial resources required and the opportunity costs of reducing national cervical cancer incidence through primary, secondary, and tertiary prevention195.

6. Treatment and Prognosis
6.1 Treatment
Cervical cancer is primarily a preventable disease, and early detection is strongly associated with significantly improved survival. Preventing cervical abnormalities from progressing into invasive cancer is crucial. The treatment (prevention) principle is to remove precancerous lesions and treat the transformation zone of the cervix196. This can be achieved through ablative procedures (thermal ablation and cryotherapy) and surgical procedures such as conization and Large Loop Excision of the Transformation Zone (LLETZ or LEEP)196. During screen-and-treat visits, women who test positive for pre-cancerous lesions and are eligible for treatment are subjected to either of the following: thermal ablation, conization, LLETZ (LEEP), cryotherapy, etc., to remove precancerous tissues62,140,141,197,198. Thermal ablation, an alternative to cryotherapy, may be a better choice for low-resource countries. Its advantages include portability (battery-powered), lower costs, and simpler operation. A limitation of thermal ablation is that it does not involve lesion biopsy199. Multiple studies showed that thermal ablation causes little or no pain during the treatment and no severe adverse events (AEs) weeks afterward, making it a safe option accepted by women in such settings200,201. One-year follow-up after thermal ablation, the successful cure rate was 96%202, 39%203, and 39.0% among WLWH and 65.2% among women without HIV62. Overall, WLWH tend to have a higher risk of CIN2+ recurrence after thermal ablation62,203.

Cervical cancer treatment typically involves surgery, radiotherapy, and chemotherapy. Women with early-stage cancer usually undergo surgery198,207, but many are diagnosed at advanced stages due to a lack of early screening166-169. Chemoradiation is crucial, especially for advanced cases198,207. In Africa, patients often receive radiotherapy, chemotherapy, or both, and brachytherapy is also used198,207,208. A recent Zimbabwean study utilized high-dose Cobalt-60 for brachytherapy, achieving a 75% complete tumor response at six weeks and a 23% partial response. At one-year follow-up, 40% showed a response, decreasing to 19% after two years209. However, there are more problems associated with treatment, such as financial burden, as reported by Rubagumya et al.210, and access to radiotherapy, which has been extensively reviewed by Ponce et al.211. The waiting time for chemoradiation may be significantly associated with disease progression, as there is limited equipment. An Ethiopian study demonstrated that, compared to women who initiated radiotherapy ≤60 days after diagnostic confirmation, the odds of tumor progression to a higher stage were three times higher in women who commenced radiotherapy between 120-179 days and ≥180 days212.

In addition to logistical challenges affecting treatment effectiveness, patients also endure significant physiological burdens from the therapies. Recent Zimbabwean studies on cisplatin in women with cervical cancer show peripheral neuropathy and ototoxicity as common AEs. These AEs risks are higher among those with existing conditions like high blood pressure or kidney disease213. In a South African study, patients experienced complete ototoxic hearing loss 1 month after treatment. The most common AEs were sensorineural hearing loss and high-frequency tinnitus214. These findings emphasize the need for clinicians to carefully monitor and manage treatment-related side effects to ensure patient safety and quality of life.

6.2 Prognosis
Quality care and management are usually associated with a good prognosis. A population study conducted in SSA revealed that countries with a lower Human Development Index (HDI) had a significantly poorer survival rate for stage I-II cervical cancer patients than those with a higher HDI215. An observational study examined treatment adherence and survival rates. It found that early-stage patients were more likely to follow guidelines than late-stage patients. Deviations from guidelines, whether minor or major, were linked to poorer survival in patients with FIGO stage I-III. Additionally, cancer-directed therapy without curative intent, or no therapy at all, was associated with significantly worse outcomes216.

Surgery or chemoradiation may improve survival rates, offering hope for some patients. DeBoer et al. found that the three-year event-free survival rates were 90% with radical hysterectomy (95% CI = 72-97%), 66% with chemoradiation (95% CI = 55-75%), and 12% with chemotherapy only (95% CI = 6-20%)207. Patients should be encouraged to receive chemoradiation as the first-choice therapy rather than radiation alone, as it has a relatively higher overall survival rate217. A meta-analysis of cervical cancer survival rates in East African countries showed pooled one-year, two-year, three-year, four-year, and five-year survival rates of 84%, 71%, 50%, 39%, and 36%, respectively218. Additionally, a Moroccan study concluded that the 5-year overall survival rate ranged from 41.3% to 73.6%, while the 3-year overall survival rate ranged from 64.9% to 78.3%. The study also linked survival to age, noting that older patients tend to have lower survival rates166. In a Botswana study, the 5-year overall survival rates after chemoradiation were 56.8% for women without HIV and 55.1% for WLWH. The study concluded that regardless of HIV status, hemoglobin levels and stage at diagnosis were associated with survival219. The above finding was also confirmed in the same country; well-managed HIV had no significant effect on either chemoradiation, “standalone” radiotherapy, or palliative radiotherapy220. Considering this, HIV patients should strictly adhere to antiretroviral therapy, as this increases their chances of survival.

The way forward for Africa
Achieving cervical cancer elimination in Africa requires moving from policy to action, addressing structural barriers, with future efforts grounded in feasible implementation. These efforts should address HPV vaccine delivery issues by adopting and exploring cost-effective vaccination schedules, developing nationwide distribution strategies, and partnering with vaccine manufacturers. Future research can focus on validating the long-term efficacy of the single- or extended-duration two-dose regimen in both the HIV population and the general population. Future efforts also require governments to integrate self-sampling into screening programs, introduce health insurance covering screening and treatment to address existing low screening rates, and strategically invest in decentralized diagnostics and treatment by equipping regional hospitals with local radiation oncology centers and advanced diagnostic laboratories, thereby reducing reliance on external processing and improving availability and access. This infrastructure must be paired with specialized cancer care centers of excellence. These combined efforts will make elimination a tangible reality.

Methods
This study analyzes population-level data extracted from the IARC Global Cancer Observatory, WHO Immunization Data Portal, and Gavi, the Vaccine Alliance. To ensure technical consistency, data were harmonized by standardizing country names using ISO-3 codes and age-standardizing cancer rates to the World Standard Population. Descriptive analysis and visualizations were conducted in R (v4.4.2) using the dplyr and ggplot2 packages. For full reproducibility, the processed datasets and custom analysis code are available (See Data and Code Availability).

Data Availability
The compiled and processed dataset generated from these sources for the analysis and visualizations in this study has been deposited in the Zenodo repository under accession code doi.org/10.5281/zenodo.17722637 (https://doi.org/10.5281/zenodo.17512055). Source data are provided with this paper.

Code Availability
R software (version 4.4.2) was used for all analyses and visualization. The custom code used in this study has been deposited in the Zenodo repository under accession code doi.org/10.5281/zenodo.17534613 (https://doi.org/10.5281/zenodo.17511134).

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_2": "The authors present a review of cervical cancer overview and strategies in Africa. This is a very comprehensive review, well written and clear format to follow. I have a few comments for the authors: There is some repetition with the WHO goals (lines 116-117) and I think minimizing this would be helpful. In figure 4, please correct the spelling of \"unavailable\". Authors advise educating/training more healthcare professions, but what is the mechanism they propose to do this? Advocating for additional resources is simple but insight in how to supply this is key.", "reviewer_3": "This interesting manuscript reporting on review of recent advancements in the screening, treatment, and prognosis of cervical cancer, and describing the epidemiology of HPV and cervical cancer in sub-Saharan Africa. The manuscript is well written, it its objectives are clearly outlined, and the content aligns well with the goals of the manuscript. To improve the quality of this manuscript before its publication, some comments require consideration by the authors. In the “Epidemiology” heading (lines 54 and 55), global health data are provided for the year 2020. The authors could use most recent data, such as 2022 data. In figure 1, the authors summarize the crude rate estimated prevalence data for cervical cancer in Africa (per country), with the aim to compare the prevalence across countries. However, it is not clear what statistical methods were employed to ensure comparability between countries. This is important because not all countries are affected homogeneously by cervical cancer, the susceptibility to the disease can vary between populations (for example, according to the socio-economic status, according to the HIV status,…), cervical cancer screening and HPH vaccination coverage may vary between population, and other factors that may contribute to the different prevalence rates should be accounted for to make such a Figure (Figure 1) readable and relevant. In the same way, while there is mention that the data source for Figures 2 and 3 (about cervical cancer incidence and mortality rates) is the GCO, the authors do not specify in what year the data were obtained from each country. Were data from all countries obtained in the same year (if so, what year was it?), or were they obtained in different years (in which case, does it make sense to compile them in such figures?). Even if the data were reported from the same year, how relevant is it to present crude rates, as opposed to age-adjusted rates for example? Could the authors explain how interpretable are these figures (Figures 2 and 3)?. In the “HPV prevalence and genotype distribution” heading, the authors acknowledge that “The prevalence and genotype distribution of HPV vary by geographic region, age, and the burden of HIV” then they describe the results obtained in various African settings from different studies. A key factor that may explain the differences observed across studies, is the type of HPV assay used in these studies, the positivity cut-off chosen by manufacturers, the HPV detection technique, the specimen collection kits and technique, the specimen storage and transportation method, the time interval between specimen collection and testing, among others. The manuscript lacks detailed information about these key factors that may affect HPV prevalence and genotype distribution, and the authors are encouraged to include additional columns in the Supplementary Table 1 and provide relevant information when available, which is critical for this review. This information is partly provided in Supplementary table 2, however, it does not specify how these different assays have affected the results obtained by authors. In addition, there are recent studies about HPV prevalence and type distribution in Africa that are not included in this supplementary Table 1. Please update accordingly. In the “HPV Vaccination” heading the manuscript lacks discussion of some important aspects of HPV vaccination that are critical for such a review. The description of different immunization strategies (school-based approach, community-based approach, mother-and-daughter approach, a combination of these, etc…) should be included, with specific reference to those that are more relevant to the African context. In addition, the effect of HIV (whose prevalence is higher in Africa) on HPV vaccination and some other consideration that are specific to Africa should be further discussed here. In the “cervical cancer screening” heading, it writes in lines 196-198: “Zambia, in response to eliminating cervical cancer, has implemented a screening program that screening every five years for women aged 30-59 years and 25-59 living with HIV every three years if not diagnosed positively in previous screening.” This sentence is a bit confusing and should be rephrased for clarity. In lines 200-202, the authors state: “However, it was supplemented with HPV testing, which improved the screening quality as 201 VIA-negative but HPV-positive patients could be detected and were asked to follow up after a 202 year.” What do they mean by “screening quality” in this sentence? Do they refer to the reduction of false-negative results with a screening strategy combining VIA and HPV testing? Please clarify. In lines 182-185, in addition to the ACS’s screening guidelines, the authors should consider including the WHO recommendations for cervical cancer screening. In lines 206-217, the combination of HPV testing and other screening tools in the context of LMICs. While cytology-based screening approaches have failed to be implemented on a large scale in such settings, the authors refer to demonstration projects assessing screening strategies in which cytology testing is used as a secondary screening tool. The feasibility of scaling up such strategies in the context of LMICs remain uncertain and should be discussed in this paragraph. Are cost-effectiveness studies If cost-effectiveness studies comparing these screening strategies been performed, this information should be included in this chapter of the manuscript, Furthermore, other secondary screening methods that have potential to be more relevant to LMICs, such as artificial intelligence enhanced VIA are being evaluated and should be referenced to in this section of the manuscript. In lines 255-263, the authors discuss the potential of self-sampling in improving cervical cancer screening coverage. This paragraph may benefit from additional information helping reader to compare provider-collected sampling and self-collected sampling, including the advantages and potential limitations of each method in the African context. Right before the “treatment” heading, the authors should consider including a section about cervical cancer diagnosis, to discuss issues such as late-stage diagnosis, lack of knowledge about cervical cancer among population and healthcare providers, and challenges associated with cervical cancer diagnosis in Africa. A general observation is that information about northern Africa is limited in this review. As a result, the authors should consider either focusing their manuscript about sub-Saharan Africa, or including relevant information wherever necessary about Northern Africa, since this region is different (at least to an extent) from sub-Sahara African in terms of health system and infrastructures, human and financial resources, sociodemographic and cultural characteristics. Another general observation is that some recent publications that are relevant to this overview have not been included. An example is the following: Manga SM, Ye Y, Nulah KL, Manjuh F, Fokom-Domgue J, Scarinci I, Tita AN. Human Papillomavirus Types and Cervical Cancer Screening among Female Sex Workers in Cameroon. Cancers (Basel). 2024 Jan 5;16(2):243. doi: 10.3390/cancers16020243. PMID: 38254734; PMCID: PMC10814164. Therefore, the authors are recommended to review the literature again and update their reference list accordingly. Thank you.", "reviewer_4": "The review is detailed and comprehensive in scope but omitted recent works regarding the elimination agenda. In Nigeria, data concerning HPV vaccination showed that 12.3 million girls aged 9-13 were vaccinated over 9 months. I have tracked a few typo errors. The conspicuous missing ones are in the body of the manuscript. Overall, it is a welcome addition to the body of knowledge, and I support its acceptance after correction. I do not need to see it again.", "reviewer_5": "The aim of this review was to discuss prevention strategies and approaches for cervical cancer adapted to sub-Saharan Africa context. This is an interesting manuscript that reviews different primary, secondary and tertiary prevention option. The authors have done an important job of exploring the different options available, but I find it difficult for the reader to know which approaches are feasible (in a LMIC context) and which are not (i.e. methylation, which is widely presented here, is not currently feasible on a large scale due to its technical complexity, while the genotyping approach is only briefly explored, even though it is one of the most feasible). Maybe the paper could be potentially improved considering the following comment: 1. At present, the term HR-HPV tends to be abandoned, given that LR (Low-risk HPV) are not at risk of cancer. The current preferred term is oncogenic (carcinogenic) HPV and the terms low risk and high risk should be avoided. 2. Primary prevention (Target 1 WHO) with the different vaccine is well-explored, but at the end of this chapter it would be interesting to explain: a. Why a single dose of HPV vaccine is not currently a standard of care, as a single-dose regime may be particularly relevant in LMIC (maybe also in HIC). The authors must explain what evidence is lacking for this to become a standard treatment b. GAVI (probably also UNITAIDS) strategies, as well as the current coverage rate of HPV vaccine in sub-Saharan Africa should be reported. 3. Secondary prevention (Target 2 WHO) needs to include: a. the concepts of “Screen and Treat” as well as “Visual Assessment for Treatment (VAT)” b. HPV primary screening and triage with the different genotype should be discussed more in detail. It is currently one of the approaches favored by the WHO. c. VIA is only recommended in centers that already have VIA in place, but the WHO no longer recommends VIA given its poor performance. HPV screening should be given priority in new centers that are opening or are about to open. 4. Tertiary prevention (Target 3 WHO) is unfortunate not analyzed much. Table reporting success of thermal ablation in different setting would be helpful, as well as performance of TA in women living with HIV would also helpful. Extended surgery in a context have poor access to radiotherapy should be explain."}, "author_response": "RESPONSESTOTHEREVIEWERS. Reviewer2:Thankyouforyourcomments,whichgavedepthtoourmanuscript. “There is some repetition with the WHO goals (lines 116-117) and I think minimizing thiswouldbehelpful.” Re: We have reduced this repetition to “HPVvaccinationisanessentialpreventivemethod forcervicalcancer,” which is found on page 6, line 132. “InFigure4,pleasecorrectthespellingof\"unavailable\".” Re: Thanks for bringing this to our attention. We rectified the spelling in the original Figure 4, now Figure 6, which can be found on page 44. “Authorsadviseeducating/trainingmorehealthcareprofessions,butwhatisthe mechanism they propose to do this? Advocating for additional resources is simple but insight in how to supply thisiskey.” Re: Thank you for this comment. We agree that advocating for additional resources is simple. In response to your comment, we have proposed several mechanisms aimed at training (educating) healthcare providers. These interventions include training healthcare providers in emotional intelligence and effective communication with patients, using culturally relevant materials on cervical cancer. Additionally, we highlighted the use of mobile health educational services that prioritize efficient supervision to ensure healthcare providers develop competencies rather than just general knowledge. Lastly, we advocated for funding to support healthcare providers' continued education, aiming to enhance local capacity. We also suggest that local governments initiate long-term funding for these interventions. These revisions can be found on page 15, lines 416-441. Reviewer3:Thankyouforyourdetailedcomments,whichaddedsignificantvalueto ourmanuscript. “Inthe“Epidemiology”heading(lines54and 55), global health data are provided for theyear2020.Theauthorscouldusemostrecentdata,suchas2022data.” Re:Thankyou.Wefoundtherecentdatafor2022andincludeddataforAfricaaswell.“An estimated660,000newcases ofcervicalcancer and350,000deaths occurredin2022; 125,699newcasesand80,614deathswereinAfrica.”Thiscanbefoundonpage3,lines57- 58. “Infigure1,theauthorssummarizethecruderateestimatedprevalencedatafor cervical cancer in Africa (per country), with the aim to compare the prevalence across countries. However, it is not clear what statistical methods were employed to ensure comparability between countries. This is important because not all countries are affected homogeneously by cervical cancer, the susceptibility to the disease can vary between populations (for example, according to the socio-economic status, according to theHIVstatus,…),cervicalcancerscreeningandHPHvaccinationcoveragemayvary between population, and other factors that may contribute to the different prevalence ratesshouldbeaccountedfortomakesuchaFigure(Figure1) readableandrelevant.” Re: Thank you for the comment on prevalence. Your comment prompted us to recheck the data found on the GLOBOCAN site. We noticed the crude rate was an inappropriate representation of prevalence. We changed the prevalence measure to Proportion (World) per 100,000inFigure1,onpage39.“Theprevalenceestimatesfor2022werecomputedusing sex-, site-, and age-specific ratios of incidence to 1-, 3-, and 5-year prevalence from Nordic countries for 2006–2015. These ratios were scaled using Human Development Index (HDI) ratios.”Wehopethismakesitmoretransparent.Also,weagreethatprevalenceisaffectedby several factors. We briefly added some factors, such as geographic variation, socioeconomic factors, existing STIs such as HIV, etc., on page 5, lines 99-100. “Inthesameway,whilethereismentionthatthedatasourceforFigures2and3(about cervical cancer incidence and mortality rates) is the GCO, the authors do not specify in what year the data were obtained from each country. Were data from all countries obtained in the same year (if so, what year was it?), or were they obtained in different years (in which case, does it make sense to compile them in such figures?). Even if the data were reported from the same year, how relevant is it to present crude rates, as opposed to age-adjusted rates, for example? Could the authors explain how interpretable are thesefigures(Figures2and3)?” Re: Thank you for bringing this to our attention. We, the authors, discussed the relevance of presenting crude rates as opposed to age-standardized rates. We concluded that age- standardized rates present more equitable comparisons of regions over time, which isolates the actual risk from demographic noise. All data were estimated to 2022. Methods from GLOBOCAN show that the data of most African countries were recent rates applied to 2022. However, the incidence of countries without any data was estimated according to neighboring countries. The revised Figures 2 and 3 in the figures document show the incidence and mortality rates in ASR (World) on 40 and 41, respectively, which uses the standard world population to make the figure more meaningful. “Inthe“HPVprevalenceandgenotypedistribution”heading,theauthorsacknowledge that“TheprevalenceandgenotypedistributionofHPVvarybygeographicregion,age, andtheburdenofHIV”thentheydescribetheresults obtained in various African settings from different studies. A key factor that may explain the differences observed across studies, is the type of HPV assay used in these studies, the positivity cut-off chosen by manufacturers, the HPV detection technique, the specimen collection kits and technique, the specimen storage and transportation method, the time interval between specimencollectionandtesting,amongothers.” Re: Thank you for this addition. Interestingly,wefoundastudydemonstratingadifference betweenXpertHPVandScreenFireHPVindetectingHPVamongself-sampledpatients. Thismayhaveresultedfromstoringspecimensforonetotwoyearsbeforetestingwith ScreenFire. Indeed, we found few studies on the positivity cut-off chosen by manufacturers and how some assays may have lower cut-off limits for specific genotypes, suchastheCobas 4800HPV,whichhasacut-offof40.5forHPV16,40forHPV18,andpooled12-HPV channels.Thesecanbefoundonpage5,lines101-110.Unfortunately,wedidn’tfindrelevant literatureduringourrevisioninthelineofprevalence.However,wefoundthatadjustingcut- offlimitscouldincreasethespecificityofendpointCIN2+withonly aminimaldecreasein sensitivity;thismaybehelpfulintheAfricansetting.Thisisfoundonpage12,lines331- 333. “Themanuscriptlacksdetailedinformationaboutthesekeyfactorsthatmayaffect HPV prevalence and genotype distribution, and the authors are encouraged to include additional columns in the Supplementary Table 1 and provide relevant information when available, which is critical for this review. This information is partly provided in Supplementary table 2, however, it does not specify how these different assays have affected the results obtained by authors. In addition, there are recent studies about HPV prevalence and type distribution in Africa that are not included in this supplementaryTable1.Pleaseupdateaccordingly.” Re: Thank you for the remark. We updated our supplementary literature, adding the recommended literature and literature from North Africa. In the manuscript, we mention the prevalence of North Africa on page 4, lines 83-89, and pages 4-5, lines 95-96. Furthermore, we added a new column on the age range of the study participants in Supplementary Table 1. In supplementary table two, we added the cut-off points for the assays on which we could find literature. We notice that in supplementary table 2, some assays detect a vast number of genotypes while others show a little. Our manuscript describes this limitation on page 5, lines 110-112. “Inthe“HPVVaccination”heading,themanuscriptlacksdiscussionofsomeimportant aspects of HPV vaccination that are critical for such a review. The description of different immunization strategies (school-based approach, community-based approach, mother-and-daughterapproach,acombinationofthese,etc…)shouldbeincluded,with specific reference to those that are more relevant to the African context. In addition, the effect of HIV (whose prevalence is higher in Africa) on HPV vaccination and some other considerationthatarespecifictoAfricashouldbefurtherdiscussedhere.” Re: Thank you for this recommendation. We discussed the various strategies, including school-based vaccination given to adolescents during school routine programs. Mother-to- daughter vaccination, where cervical cancer screening is done for mothers while daughters receive vaccination in the sitting. This improved knowledge of cervical cancer. Also, we mentioned community-based vaccination, where door-to-door and outreach programs are done, and the mixed strategy on pages 6-7, 158-172. Reports on the effect of HIV on HPV vaccination are limited. However,weaddedastudyinSouthAfricathatevaluatedtheimpact ofthesingle-dosevaccineonHIV-infectedgirls,concludingwithareductioninpost-vaccine HPV16/18;itstillhadlimitationsasthestudydoesnotimitateallpopulationslivingwith HIVinAfrica. These can be found on page 8, lines 204-206, and page 8, lines 218-221. “Inthe“cervicalcancerscreening”heading,itwritesinlines196-198:“Zambia,in response to eliminating cervical cancer, has implemented a screening program that screening every five years for women aged 30-59 years and 25-59 living with HIV every threeyearsifnotdiagnosedpositivelyinpreviousscreening.”Thissentenceisabit confusingandshouldberephrasedforclarity.” Re: Thank you for the suggestion. We clarified this sentence to make it simple for the reader. Zambia,inresponsetoeliminatingcervicalcancer,hasimplementedascreeningroutine everyfiveyearsforwomenaged30-59andeverythreeyearsforwomenlivingwithHIV aged25-59ifnotdiagnosedpositivelyinpreviousscreenings.Thisisfoundonpage10,lines 280-282. “In lines 200-202,theauthorsstate:“However,itwassupplementedwithHPVtesting, which improved the screening quality as 201 VIA-negative but HPV-positive patients could bedetectedandwereaskedtofollowupaftera202year.”Whatdotheymeanby “screeningquality”inthissentence?Dotheyrefertothereductionoffalse-negative resultswithascreeningstrategycombiningVIAandHPVtesting?Pleaseclarify.” Re: Thanks for the question. Screening quality in that statement may have been vague. We changedthesentencelikethis:“However,itwassupplementedwithHPVtesting,which improvedend-pointsensitivityinthedetectionofdysplasiaasVIA-negative,butHPV- positivepatientscouldbedetected.Thisadditionreducedthepotencyoffalse-negative results.WomenwithVIA-negativebutHPV-positiveresultswereaskedtofollowupaftera year.”Thisisfoundonpages10-11,lines284-287. “Inlines182-185, in additiontotheACS’sscreeningguidelines,theauthorsshould considerincludingtheWHOrecommendationsforcervicalcancerscreening.” Re: Thank you for the suggestion. We added the WHO recommendations for screening, which advocate that womenshouldbescreenedforcervicalcancerevery5–10yearsstarting atage30andwomenlivingwithHIVevery3yearsstartingatage25.Thisisonpages9-10, lines253-256. “Inlines206-217, the combination of HPV testing and other screening tools in the context of LMICs. While cytology-based screening approaches have failed to be implemented on a large scale in such settings, the authors refer to demonstration projects assessing screening strategies in which cytology testing is used as a secondary screening tool. The feasibility of scaling up such strategies in the context of LMICs remain uncertain and should be discussed in this paragraph. Are cost-effectiveness studies If cost-effectiveness studies comparing these screening strategies been performed,thisinformationshouldbeincludedinthischapterofthemanuscript,” Re: Thanks for bringing our attention to this. The feasibility of cervical cancer screening varies among nations. However, VIA is the most cost-effective, but it has the lowest sensitivity. HPV DNA testing may be long-term and cost-effective if integrated with single-visit screening. We also state that cytology and methylation for primary cervical cancer screening may not be feasible in Africa as they require infrastructure and skill. This can be found on page 13, lines 353-372. “Furthermore,othersecondaryscreeningmethodsthathavepotentialtobemore relevant to LMICs, such as artificial intelligence enhanced VIA are being evaluated and should be referenced to in this sectionofthemanuscript.” Re: Thanks for the suggestion. We improved our VIA section by adding the use of AI and smartphones. We discussed the advantages of using AI (computer/smartphone-aided); some that stood out were improved communications with patients and easier consultations among healthcare providers. Implementation may still need the training of healthcare providers and infrastructure. This revision can be found on page 11, lines 291-303. “Inlines255-263, the authors discuss the potential of self-sampling in improving cervical cancer screening coverage. This paragraph may benefit from additional information helping reader to compare provider-collected sampling and self-collected sampling, including the advantages and potential limitations of each method in the Africancontext.” Re: Thank you for the suggestion. Only a few papers have discussed the advantages and disadvantages of these screening sampling in the African context. The benefits of sampling were added to the manuscript, such as intimacy (not having to let another see their private parts) and less fear of pain. At the same time, disadvantages may include anxiety over doing the procedure right. This is provided on page 14, lines 403-406. “Rightbeforethe“treatment”heading,the authors should consider including a section about cervical cancer diagnosis to discuss issues such as late-stage diagnosis, lack of knowledge about cervical cancer among population and healthcare providers, and challenges associated with cervical cancer diagnosisinAfrica.” Re:Thanksforthesuggestion.Wediscussedandrealizedtheproposedcervicalcancer diagnosisissimilartothescreeningcoverageratesinouroriginalmanuscript;therefore,we integratedthem.MostcervicalcancerdiagnosesinAfricaarefoundintheadvancedstagesof thedisease.Reasonsforthisincludelessknowledgeaboutcervicalcancer,hencedelayin seekinghealthcare,educationallevel,livinginruralareas,income,etc,amongthepublic. Healthcareproviderslackedaccuratepatientinformationandknowledgeofthepresentation ofcervicalcancer.Onanationalscale,campaignsaboutcervicalcancerarelow.Thiscanbe foundonpages13-14,lines374-385. “AgeneralobservationisthatinformationaboutnorthernAfrica is limited in this review. As a result, the authors should consider either focusing their manuscript about sub-Saharan Africa, or including relevant information wherever necessary about Northern Africa, since this region is different (at least to an extent) from sub-Sahara African in terms of health system and infrastructures, human and financial resources, sociodemographicandculturalcharacteristics.” Re: Thanks for the suggestion. Information on North Africa was limited in our original manuscript. We added relevant information on this region. However, although the prevalence of HPV and cervical cancer may be low in these regions compared to sub-Saharan Africa, the knowledge of cervical cancer and HPV vaccination among these regions is similar. Also, a study concluded there may be a false sense of security and misconceptions among healthcare providers in countries in North Africa. We also reported on the survival rates in a North African country. These relevant information can be found on pages 4, lines 83-89; pages 4-5, lines 95-96; page 8, lines 192-194; page 13, lines 375-378; page 14, 394-397; pages 17 lines 502-505. “Anothergeneralobservationisthatsomerecentpublicationsthatarerelevanttothis overview have not been included. An example is the following: Manga SM, Ye Y, Nulah KL, Manjuh F, Fokom-Domgue J, Scarinci I, Tita AN. Human Papillomavirus Types and Cervical Cancer Screening among Female Sex Workers in Cameroon. Cancers (Basel). 2024 Jan 5;16(2):243. doi: 10.3390/cancers16020243. PMID: 38254734; PMCID: PMC10814164. Therefore, the authors are recommended to review the literature again and update their referencelistaccordingly.” Re: Thanks for bringing this to our attention. We updated our supplementary literature in supplementary table 1, adding the recommended literature and literature from North Africa. Reviewer 4: Thank you for your comments and confidence in our work. “Thereviewisdetailedandcomprehensiveinscopebutomittedrecentworksregarding the elimination agenda. In Nigeria, data concerning HPV vaccination showed that 12.3 million girls aged 9-13 were vaccinated over 9 months. I have tracked a few typo errors. The conspicuous missing ones are in the body of the manuscript. Overall, it is a welcome addition to the body of knowledge, and I support its acceptance aftercorrection.Idonotneedtoseeitagain.” Re: Thanks for bringing this to our attention. In our manuscript, we updated the literature concerningtheeliminationagenda.However,webelievedataconcerningNigeria’s vaccination falls under vaccination of girls aged 9-14 on page 6, lines 156-158. However, we mention that countries like Nigeria use a mixed vaccination strategy, which can be found on page 7, lines 170-171. We added suggested literature that mentioned that HIV influences HPV in a three-country study in Africa on pages 5-6, lines 127-130. We have also cross-checked for typos and corrected them. “Whatisthesourceofthesedocuments? UseofMiddleAfricaisuncommonasagainstCentralAfrica” Re: Thanks for highlighting the source's omission in the graphical abstract. We included the source, GLOBOCAN 2022, in the image. Middle Africa is used interchangeably with Central Africa; however, we changed to the regular Central Africa in our graphical abstract image. Reviewer 5: Thank you for the suggestions, which we agree improved the quality of our manuscript. “Theauthorshavedoneanimportantjobofexploringthedifferentoptionsavailable, butIfinditdifficultforthereadertoknowwhichapproachesarefeasible(inaLMIC context)andwhicharenot(i.e.methylation,whichiswidelypresentedhere,isnot currentlyfeasibleonalargescaleduetoitstechnicalcomplexity,whilethegenotyping approachisonlybrieflyexplored,eventhoughitisoneofthemostfeasible).” Re:Thankyouforthesuggestion.WetackledthefeasibilityofscreeningmethodsinAfrica. We discussed that VIA is the most cost-effective but has the lowest sensitivity. However, HPV DNA testing may be long-term effective and cost-effective if integrated with single- visit screening. We also state that cytology and methylation for primary cervical cancer screening may not be feasible in Africa as they require infrastructure and skill. This can be found on page 13, lines 353-372. “Atpresent,thetermHR-HPVtendstobeabandoned,giventhatLR(Low-riskHPV) arenotat riskofcancer.Thecurrentpreferredtermisoncogenic(carcinogenic)HPV, andthetermslowriskandhighriskshouldbeavoided.” Re:Thanksforbringingthistoourattention.Wehavechangedsuchtermswhereapplicable: onpage4,lines82and93;page5,line123;page9,line233;page9,line248;page11,lines 305,308,and309;andpage13,line359. “Primaryprevention(Target1WHO)withthedifferentvaccineiswell-explored, butat theendofthischapteritwouldbeinterestingtoexplain: a.WhyasingledoseofHPVvaccineisnotcurrentlyastandardofcare,asasingle-dose regimemaybeparticularlyrelevantinLMIC(maybealsoinHIC).Theauthorsmust explainwhatevidenceislackingforthistobecomeastandardtreatment b.GAVI(probablyalsoUNITAIDS)strategies,aswellasthecurrentcoveragerateof HPVvaccineinsub-SaharanAfricashouldbereported.” Re:Thankyouforthesecomments,whichsignificantlyimprovedthissection.IntheAfrican context,asingledoseisusedoften.However,weagreeitisstillnotastandardofcare.We discussthatthefollow-upperiodsarelimited(approximately24-36months),andthelong- termprotectionover10yearshasnotbeenfullyvalidated.Wealsomentionthatstudies primarilyassesstheprotectiveeffectbasedonimmunogenicitydataratherthanclinical endpoints,suchascervicalcancerincidence.Thisisfoundonpage8,lines212-216. WebrieflymentionedtheGAVIAllianceandincludedanimageofthecountrieseligiblefor GAVIfunding,specificallythosewithfundingspecifictoHPVVaccination.Thiscanbe foundonpage6,lines140-142,andinFigure5onpage43. “Secondaryprevention(Target2WHO)needstoinclude: a.theconceptsof“ScreenandTreat”aswellas“VisualAssessmentforTreatment (VAT)” b.HPVprimaryscreeningandtriagewiththedifferentgenotypeshouldbediscussed moreindetail.ItiscurrentlyoneoftheapproachesfavoredbytheWHO. c.VIAisonlyrecommendedincentersthatalreadyhaveVIAinplace,buttheWHOno longerrecommendsVIAgivenitspoorperformance.HPVscreeningshouldbegiven priorityinnewcentersthatareopeningorareabouttoopen.” Re:Thanksforthissuggestedadditiontothissection.Weagreethattheadditionofthis improvedourmanuscript.Thescreenandtreatandscreen,triage, andtreatapproacheswere discussedextensively.Inthe“screenandtreat”treatment,thedecisionisbasedonlyona positiveprimaryscreeningtestwithoutasecondarytest.Incontrast,inthe“screen,triageand treatapproach,”thedecisiontotreatisbasedonapositiveprimaryscreeningtestfollowedby apositivesecondtest(a“triage”test),withorwithoutahistologicallyconfirmeddiagnosis. WealsomentionedVAT,“visualassessmentfortreatment,”isdoneafterpositiveprimary resultsusingvisualinspectiontodetermineeligibilityforablativetreatment.Thesecanbe foundonpage10,lines257-269. WealsodescribedHPVgenotypingastriage.HPVpartialgenotypingidentifiesthe carcinogenictypesofHPV,mainlyHPV16and18,whereasextendedgenotypingdetectsa broaderrangeofcarcinogenicHPVtypes,enablingbetterriskstratification.Wementionedin theoriginalmanuscriptthatHPVgenotypingincreasessensitivityindysplasiadetection (page12,lines321-329).Wealsonotedthatadjustingcut-offlimitsforHPVgenotyping assayscanimprovespecificitywithminimalsensitivitylossforCIN2+.Thesechangescanbe foundonpage11,lines305-310,andpage12,lines331-333. We further discussed that although VIA is more cost-effective and is being improved by the addition of smartphone and AI-aided testing, WHO recommends a swift transition to HPV DNAtesting.Thiscanbefoundonpage11,lines303-304. “Tertiaryprevention(Target3WHO)isunfortunatenotanalyzedmuch.Table reportingsuccessofthermalablationindifferentsettingwouldbehelpful,aswellas performanceofTAinwomenlivingwithHIVwouldalsohelpful. Extendedsurgeryinacontexthavepooraccesstoradiotherapyshouldbeexplain” Re:Thankyouforthesuggestion.Weagreethattertiarypreventionisnotmentionedmuch, astherearelimitedrecentstudiesonthis.We,however,addedatablereportingthe acceptabilityrateandadverseeffectofthermalablation,whichisinthetabledocument.We alsomentionthecurerateofthermalablationinwomenlivingwithHIV,whichislowerthan inthegeneralpopulation,asrecurrenceofdysplasiawascommon.Thiscanbefoundonpage 16,lines457-461. Unfortunately,wefoundnoliteratureonextendedsurgeryintheAfricancontextofpoor accesstoradiotherapy."}, {"round": 2, "reviewer_comments": {"reviewer_2": "I have reviewed the authors responses and feel they have appropriate adjusted the manuscript or addressed the reviewers' comments/suggestions.", "reviewer_3": "The authors have done a good work in providing appropriate responses to my comments and edited the manuscript accordingly. The revised version of the manuscript is now acceptable to me.", "reviewer_6": "General Comments The authors have compiled a good review that touches on one of the most pressing public health challenges for the SSA region. A few comments for the authors to improve their article -The authors sometimes write too generalized statements, I suggest they are specific and support statements with data -Authors are encourages to carry one message /theme within each paragraph to ensure flow of information for ease readability, A revision is needed -When describing the cervical cancer burden in SSA, Authors should not use Morocco as an example to highlight the status of the burden or current progress, clearly from the illustration in the abstract Eastern and Southern Africa are the high burdened regions and therefore citations from those countries demonstrates the general landscape within SSA Abstract I’m not sure if the illustration should be placed in the abstract of the paper. May you please provide an in text citation of the illustration such as (Figure 1) Introduction L32- I think the authors wanted to write “lack of access to timely treatment” and wrote access to timely treatment is linked to poor prognosis L450-46-The authors statement suggest that developed countries have reached certain milestones due to effective vaccination strategies something that SSA countries can emulate, however your statement lacks data in numbers to support it L60-61-The authors should familiarise themselves with common terminology used to describe African regions, where authors write middle Africa it is “Central Africa” and they should write the regions in capital letters such as Southern/Eastern Africa L66-LMICs has already been defined in L-46 no need to write it in full again L92-The authors provide us with a comprehensive review of literature, however they do not do justice to the significance of HPV35 in cervical cancer carcinogenesis among African women. Although among the top 5 causes of CaCx, HPV35 is not covered by the available commercially licenced vaccines L99-100-While it is commendable that authors have highlighted the various socioeconomic issues contributing to the high HPV prevalence in SSA. I would suggest that they do not dwell on technical issues such as the choice of testing platform and specimen management. The platforms available in Africa are less or more the same with those used in other world regions where prevalence is low and therefore there is not much value from such a factor I terms of effect on prevalence L127-130- The statement lacks the names of the prevalent genotypes L183-correct statement, I think you wanted to write:” including the lack of political will” L192-194-Rewrite statement, school going children need education on HPV vaccination instead of training as you mentioned in your text L198-200 You statement seems to suggest that , the COVID-19 vaccination intervention could have played a role in increasing vaccine hesitancy among HPV vaccine candidates, however it is not coming out clearly in you statement, may you rewrite for clarity L226-228-Authors seem to suggest that acute infections such as malaria and COVID-19 have interrupted HPV vaccination programmes in Africa. Without examples it is difficult for the reader to see the role played by these diseases, particularly Malaria. I suggest you highlight how emergencies such as disease outbreaks or humanitarian crises ca affect programmatic implementation of HP vaccination and then cite COVID-19 as an example L271-274-Please provide a citation for the statement L307-311 Same as above L365-What does the author mean by “ HPV Xpert is an emerging technology, it has been around for some time and is widely used, it cannot be considered an emerging technology , we can only talk of scaling up the use and ensuring availability of cartridges for HPV testing L373-386 and L386-398 –Basically share the same content. May you combine into one concise paragraph L399-410-Considering the focus of this paper and the need to offer recommendations to policymakers within the cervical cancer prevention and control space, I feel the authors have not done justice to HPV self-collection. May we have more recommendations on how governments can introduce and integrate self-sampling into national screening programmes and the associated benefits of the intervention. L404- I would replace intimacy with autonomy L411-415-This paragraph is isolated and does not belong where it is, may you revisit and make necessary changes L416-441-The text in this paragraph is not related with the subheading titled ‘Screening and Diagnosis”, please revisit and adjust accordingly L485-Clinicians should pay attention to this, this sentence is incomplete, please rewrite it Recommendations -The authors should offer actionable recommendations as opposed to generalized statements, for instance they mention that there is need to invest in infrastructure and manpower to avoid sending samples abroad-which samples are send abroad, Are they HPV samples or Cytology samples? -Since the there is a triple elimination approach to cervical cancer elimination, I suggest the recommendations should follow • Vaccination • Screening • Treatment References Check the journal requirements for referencing and align with the instructions. I have noticed that almost all your website references are improperly cited since they do not either have the url or date of accessioning", "reviewer_7": "I co-reviewed this manuscript with one of the reviewers who provided the listed reports. This is part of the Nature Communications initiative to facilitate training in peer review and to provide appropriate recognition for Early Career Researchers who co-review manuscripts."}, "author_response": "Reviewers' comments: Reviewer #2 (Remarks to the Author): I have reviewed the authors responses and feel they have appropriate adjusted the manuscript or addressed the reviewers' comments/suggestions. Re: Thank you for your efforts and confidence in the revision of the manuscript. Reviewer #3 (Remarks to the Author): The authors have done a good work in providing appropriate responses to my comments and edited the manuscript accordingly. The revised version of the manuscript is now acceptable to me. Re: Thank you for your efforts and confidence in the revision of the manuscript. Reviewer #6 (Remarks to the Author): General Comments The authors have compiled a good review that touches on one of the most pressing public health challenges for the SSA region. A few comments for the authors to improve their article The authors sometimes write too generalized statements, I suggest they are specific and support statements with data Authors are encourages to carry one message /theme within each paragraph to ensure flow of information for ease readability, A revision is needed Re: Thank you for the suggestion. We have revised the manuscript to make sure the flow and readability are as easy as possible, to the best of our ability. When describing the cervical cancer burden in SSA, Authors should not use Morocco as an example to highlight the status of the burden or current progress, clearly from the illustration in the abstract Eastern and Southern Africa are the high burdened regions and therefore citations from those countries demonstrates the general landscape within SSA Re: Thank you for the suggestions. We have updated and added studies that highlight the current status and progress of cervical cancer in these regions. These additions can be found on page 15, lines 442-446, and page 20, lines 608-611. However, in response to the suggestion by a previous reviewer to include North Africa for comprehensive African coverage, we maintain the studies on Morocco in the prognosis section, on pages 20-21, lines 611-615. Abstract I’m not sure if the illustration should be placed in the abstract of the paper. May you please provide an in text citation of the illustration such as (Figure 1) - Re: We sincerely appreciate your concern regarding this matter. Although your suggestion was somewhat unclear, we would like to clarify that our graphical abstract (Page 2) is carefully designed to highlight the most vital aspects of the document, including key points on vaccination, screening, and treatment strategies. Additionally, it effectively presents crucial data on the incidence and mortality rates of cervical cancer across Africa, as shown in Figures 2 and 3. We hope this explanation clarifies the purpose and value of the illustration, reassuring you of its significance. Introduction L32- Ithinktheauthorswantedtowrite“lackofaccesstotimelytreatment”andwrote access to timely treatment is linked to poor prognosis Re: Thank you for drawing our attention to this. We corrected this according to your suggestion on Page 2, Line 37 in the image. L450-46-The authors statement suggest that developed countries have reached certain milestones due to effective vaccination strategies something that SSA countries can emulate, however your statement lacks data in numbers to support it Re: Thank you for this suggestion, it improved the facts of our paper. We provided factual examples from Australia where the decline of cervical abnormalities was halved after seven years, and also in the U.K., where there was a decrease in high-grade cervical abnormalities and cervical cancer. These changes can be found on Page 3, Lines 49-56. L60-61-The authors should familiarise themselves with common terminology used to describe African regions, where authors write middle Africa it is “Central Africa” and they should write the regions in capital letters such as Southern/Eastern Africa Re: Thank you for bringing our attention to this. We have changed the terms accordingly. These changes can be found on Page 5, lines 101-103 L66-LMICs has already been defined in L-46 no need to write it in full again Re: Thank you. This has been changed and can be found on Page 4, line 75 L92-The authors provide us with a comprehensive review of literature, however they do not do justice to the significance of HPV35 in cervical cancer carcinogenesis among African women. Although among the top 5 causes of CaCx, HPV35 is not covered by the available commercially licensed vaccines Re: Thank you for this suggestion. It has improved the manuscript significantly. We discuss that HPV 35 is one of the most prevalent types in Africa, both in the general population and people living with HIV. We also suggested considering HPV 35 in vaccine development. These changes can be found on Pages 5, Lines 105-114; page 6, Lines 145-149, and Lines 151-155. L99-100-While it is commendable that authors have highlighted the various socioeconomic issues contributing to the high HPV prevalence in SSA. I would suggest that they do not dwell on technical issues such as the choice of testing platform and specimen management. The platforms available in Africa are less or more the same with those used in other world regions where prevalence is low and therefore there is not much value from such a factor I terms of effect on prevalence Re: Thank you for the suggestion. Although previously requested by a previous reviewer and following deliberate discussion among authors, including our African-based author, we focused less on the technical aspects. However, we acknowledge that methodological factors may slightly affect the reported prevalence. These changes can be found on page 5, lines 117-126. We hope these changes align well with your suggestions. L127-130- The statement lacks the names of the prevalent genotypes Re: Thank you for this suggestion. We included the names of the said prevalent genotypes on Page 6, Line 144. L183-correctstatement,Ithinkyouwantedtowrite:”includingthelackofpoliticalwill” Re: Thank you. We have corrected this on Page 8, lines 210-211. L192-194-Rewrite statement, school going children need education on HPV vaccination instead of training as you mentioned in your text Re: Thank you for the correction. This has been rectified on Page 8, Lines 221-222. L198-200 You statement seems to suggest that , the COVID-19 vaccination intervention could have played a role in increasing vaccine hesitancy among HPV vaccine candidates, however it is not coming out clearly in you statement, may you rewrite for clarity Re: Thankyou.Thishasbeenrewrittenas“TherecentCOVID-19 pandemic also hindered the promotion of HPV vaccination programs as the emergency-approved COVID-19 vaccine led to misinformation about its safety, further contributing to vaccine hesitancy (delayed acceptanceorrefusalofvaccinationdespiteavailableservices).”Thiscanbefoundonpages8 and 9, Lines 226-229 L226-228-Authors seem to suggest that acute infections such as malaria and COVID-19 have interrupted HPV vaccination programmes in Africa. Without examples it is difficult for the reader to see the role played by these diseases, particularly Malaria. I suggest you highlight how emergencies such as disease outbreaks or humanitarian crises ca affect programmatic implementation of HP vaccination and then cite COVID-19 as an example Re: Thank you for this input. We have revised this section as suggested, stating that during humanitarian crises or severe outbreaks, such as COVID-19, there may be a shortage or interruption in the supply of vaccines, which can affect vaccination schedules. This can be found on Pages 9-10, Lines 258-266 L271-274-Please provide a citation for the statement Re: We provided a citation for the statement on Page 11, Line 313 “Dzinamarira,T., Moyo, E., Dzobo, M., Mbunge, E. & Murewanhema, G. Cervical cancer in sub-Saharan Africa: an urgent call for improving accessibility and use of preventive services. Int J Gynecol Cancer 33, 592-597 (2023). https://doi.org/10.1136/ijgc-2022-003957” L307-311 Same as above Re: We also provided the citation for the statement on Pages 10-11, Line 292-295 “Stoler, M. H., Parvu, V., Yanson, K., Andrews, J. & Vaughan, L. Risk stratification of HPV- positive results using extended genotyping and cytology: Data from the baseline phase of the Onclarity trial. Gynecol Oncol 174, 68-75 (2023). https://doi.org/10.1016/j.ygyno.2023.04.022” L365-Whatdoestheauthormeanby“HPVXpertisanemergingtechnology,ithasbeen around for some time and is widely used, it cannot be considered an emerging technology , we can only talk of scaling up the use and ensuring availability of cartridges for HPV testing Re: Thank you for the correction. We revised this according to your suggestion, clarifying the scaling of the assay usage. The change can be found on pages 15-16, Lines 430-433. L373-386 and L386-398 –Basically share the same content. May you combine into one concise paragraph Re: Thank you for the suggestion. We tried our best to combine the contents of the paragraphs into a concise paragraph. We transition from late diagnosis to screening coverage and the factors that influence both. We added peculiar additions such as the trends over two decades, which discuss a rise in coverage in Southern African countries, a slight increase in Eastern African countries, and a slight decrease in Central and Western African countries. These changes can be found on pages 15-16, lines 441-482. L399-410-Considering the focus of this paper and the need to offer recommendations to policymakers within the cervical cancer prevention and control space, I feel the authors have not done justice to HPV self-collection. May we have more recommendations on how governments can introduce and integrate self-sampling into national screening programmes and the associated benefits of the intervention. Re: Thank you for this suggestion. We discussed the barriers associated with self-sampling and explored how the government can introduce self-sampling in national screening programs. This collaboration with various agencies aims to improve theaffordabilityand availabilityofsamplingkits,aswellasintroduceinsurance,whichwillenhancethecoverage ofscreening.Thesechangescanbefoundonpages17,499-510. L404- I would replace intimacy with autonomy Re: Thank you. We replaced the word as suggested on Page 17, Line 491 L411-415-This paragraph is isolated and does not belong where it is, may you revisit and make necessary changes Re: We introduced a new subheading, “StrengtheningScreeningCoverage,Capacity,and Sustainability,”andplacedthisunderthesubheading.Thiscanbefoundonpage17,Lines 511-514 L416-441-Thetextinthisparagraphisnotrelatedwiththesubheadingtitled‘Screening andDiagnosis”,pleaserevisitandadjustaccordingly Re: We placed this section under the newly added subheading “Strengthening Screening Coverage,Capacity,andSustainability.”Thischangecanbefoundon Page 17-18, Lines 515- 542. L485-Clinicians should pay attention to this, this sentence is incomplete, please rewrite it Re: Thank you for this suggestion. For more clarity, we merged it with the previous sentence. “Thesefindingsemphasizetheneedforclinicianstocarefullymonitorandmanagetreatment- related side effects to ensure patient safety and quality of life.” This change can be found on Page 20, Lines 589-591. Recommendations The authors should offer actionable recommendations as opposed to generalized statements, for instance they mention that there is need to invest in infrastructure and manpower to avoid sending samples abroad-which samples are send abroad, Are they HPV samples or Cytology samples? Re: Thank you for your suggestion. We specified the kind of samples, which includes both kinds, across different studies in Africa. The studies are listed below; they are also included in our supplementary tables. This change can be found on page 21, lines 631-632. “Kaba G, Stevenson A, Sakyi SA, et al. Diversity of cervicovaginal human papillomavirus (HPV) genotypes and naturally occurring E6/E7 DNA polymorphisms of HPV-16 in Ghana. TumourVirusRes.2023;15:200261.doi:10.1016/j.tvr.2023.200261” “VieiraR,MontezumaD,BarbosaC,MacedoPintoI.CervicalcytologyandHPVdistribution in Cape Verde: A snapshot of a country taken during its first HPV nation-wide vaccination campaign. TumourVirusRes.2024;17:200280.doi:10.1016/j.tvr.2024.200280” Since the there is a triple elimination approach to cervical cancer elimination, I suggest the recommendations should follow •Vaccination •Screening •Treatment Re: Thank you for your suggestions. We follow the order suggested, starting with vaccination, then screening, and finally treatment. This can be found on pages 21, lines 623-637 References Check the journal requirements for referencing and align with the instructions. I have noticed that almost all your website references are improperly cited since they do not either have the url or date of accessioning. Re: Thank you for bringing our attention to this. We have reviewed the journal's requirements and updated our references accordingly. We have checked our website citations and ensured they function properly, and all accession dates have been added. They are shown below: WHO. Cervical cancer. 2024 <https://www.who.int/news-room/fact- sheets/detail/cervical- cancer#:~:text=Key%20facts,%2Dincome%20countries%20(1> (Accessed 31 August 2024). Ferlay J, E. M., Lam F, Laversanne M, Colombet M, Mery L, Piñeros M, ZnaorA, Soerjomataram I, Bray F. Global Cancer Observatory: Cancer Today. 2024, <https://gco.iarc.who.int/today> (Accessed 2 September 2024). WHO-AFRO. African health ministers, partners urge equitable access to critical tools to curb cervical cancer threat. 2024, <https://www.afro.who.int/news/african- health-ministers-partners-urge-equitable-access-critical-tools-curb-cervical- cancer.> (Accessed 10 September 2024). Reviewer #7 (Remarks to the Author): I co-reviewed this manuscript with one of the reviewers who provided the listed reports. This is part of the Nature Communications initiative to facilitate training in peer review and to provide appropriate recognition for Early Career Researchers who co-review manuscripts. Re: We appreciate your efforts."}]

Decision letter