As previously stated, areas where cervical cancer is the leading cause of death amongst women include Sub-Saharan Africa, Melanesia (Western Pacific), South Central and South East Asia, the Caribbean and Latin America (31). In wealthier developed countries, it is recommended that screening for cervical cancer with the Papanicolaou (Pap) smear is initiated at 21 years and repeated every year until the patient is 65 years old (32). Pap smears should be performed in conjunction with HPV screening; if the test reveals no signs of cervical cancer but presence of HPV, genotyping of the HPV should be performed, which may either be followed by a colposcopy, or HPV and cytology must be repeated at a later stage (33). Table II presents the age-standardised rate (ASR) which is the number per 100,000 people diagnosed with cervical cancer in the four countries, which will be discussed below. These four LMICs (South Africa, Tanzania, India and Brazil) are also compared against China Despite its large number of new cervical cancer cases, cervical cancer only comprises 2.5% of all cancer cases (15).

The United Nations defines South Africa as an upper middle-income country with unequal distribution of wealth and a high rate of poverty (34). The 2014 South African National Cancer Registry statistics (35) for cervical cancer cases and deaths reported that the number of new observed cases in South African women was 5,735 in 2014, accounting for 16.17% of all cancers diagnosed in South African women; the ASR was 22.56 per 100,000 women (35). Analysis of the ASR and new cases by ethnic group revealed that the black population was more affected than any other group (Table III). The ‘white’ and ‘other’ population groups, which includes those of mixed ancestry, had <10% of the number of cases and an ASR <50% compared with the black population. The Asian population had the lowest number of cases and the lowest ASR. This population group is also the most economically disadvantaged and has poor access to healthcare (36). Since South Africa has the highest infection rate of HIV and the largest anti-retroviral program in the world (37), it is important to consider the influence of these two factors on cervical cancer. The total levels of HIV-related cancers have decreased following the introduction of anti-retroviral therapy; despite this, the mortality due to Acquired Immune Deficiency Syndrome (AIDS)-related illnesses is still high and has contributed to a lower life expectancy in South Africa (38). HIV is associated with abnormal cervical cytology and higher levels of HPV or numerous HPV types (34). The high prevalence of HIV in South Africa was predicted to lead to a marked increase in the incidence of cervical cancer, as it is one of the AIDS-defining illnesses, but such an increase has not occurred. Initially, prior to the introduction of anti-retroviral treatment, this was due to women succumbing to HIV/AIDS before they could develop cervical cancer; following the introduction of retroviral therapy, a decrease in the rates of all AIDS-defining cancers affected the numbers of cervical cancer cases (36).

The screening policy for cervical cancer in South Africa was established in 2000 and involves three Pap smears per lifetime starting at 30 years of age and occurring at 10-year intervals. The smear is repeated after 12 months if any abnormality is observed. If the abnormality persists or if a high-grade lesion is identified, the patient is referred for a colposcopy (39).

HPV is common among young, sexually active individuals; the infection normally clears without treatment, but recurrence is also common. Persistent infection with HR HPV genotypes leads to precancerous lesions and ultimately cervical carcinoma (39). Due to the high prevalence of transient HPV infection in young women among certain population groups, the usefulness of HPV screening as a tool for identifying those at risk of cervical cancer is limited (34). One preventive strategy for HPV infection used in South Africa is the introduction of the HPV vaccine. In 2014, a national school-based program for the HPV bivalent vaccine was introduced in all public schools, targeting girls in grade 4 (aged ≥9 years old) with a two-dose (6 months apart) schedule (40). Although a high vaccination rate was achieved in these school based programs, the effect on HPV infection rates is yet to be elucidated.

Cervical cancer accounts for 40% of all cancer cases diagnosed in women in East Africa, with the highest ASR (50.6 per 100,000 women) in Tanzania. Tanzania also ranks 13^th on prevalence of HIV infection worldwide (15). Since women infected with HIV are at an increased risk of developing cervical cancer, it is important that they are screened early and often (23,41). To combat cervical cancer, Tanzania has introduced a ‘screen and treat’ policy; the most common form of screening is visual inspection of the cervix with the naked eye following the application of acetic acid, abbreviated as visual inspection with acetic acid (VIA) (42). The acetic acid solution swabbed on the surface of the cervix (cervical epithelium) turns pre-cancerous lesions white (43). Following a positive diagnosis, the lesions are immediately treated by cryotherapy (41). Similarly to other low-income, developing countries, the rates of HPV infection are high in Tanzania; this has led to the Tanzanian Ministry of Health to initiate a school-based HPV vaccination program (44). Other factors that contribute to the high incidence of cervical cancer in Tanzania include; resource allocation (in term of distribution of trained personnel, funds and equipment in urban and rural areas nationwide), lack of resources to fulfil the needs of the entire population, sociocultural influence and a lack of political will (where leaders do not prioritise healthcare programmes and choose to divert funds and resources from screening and treatment programmes) (45). Sociocultural factors such as folklore and myths around cervical cancer screening influence the willingness of people to undergo screening (41).

In 2015, cervical cancer was the second most common cancer amongst women in India; an estimated 132,314 new cases were diagnosed and 73,337 patients succumbed to cervical cancer (46). Due to India's large population of 1.2 billion, this accounted for nearly one-fifth of all cervical cancer cases worldwide (47). It is difficult to determine an accurate ASR for India, as different cancer registries cover different areas, and ASRs vary between 9 and 40 per 100,000 women, depending on the region (47). India spends 0.9% of its gross domestic product (GDP) on healthcare, and no organised cervical cancer screening programs are available (48). Risk factors associated with cervical cancer in India include illiteracy, lack of toilets or running water inside the house, not washing genitals after sexual intercourse, age at first sexual intercourse <15 years, multiple lifetime sexual partners, widowhood and HPV (49). The prevalence of HR HPV in India ranges between 7 and 13%, and HPV 16 and 18 are the most common types of HPV in India (50). This varies by region and is also possibly influenced by culture; however, unlike in developed countries, the number of young women diagnosed with HPV is not higher than that of older women (47), suggesting that the infection is equally distributed across all age groups.

HPV testing is cheap, objective and reproducible in rural areas in India (50). However, the use of HPV testing in a ‘screen and treat strategy’ can cause problems, as the majority of HPV infections in young women do not result in cervical cancer (47). HPV cytology-based cervical cancer screening is not possible for the entire population of India due to its large size, as well as a lack of resources, trained staff and facilities. This has led to the adoption of other low-cost, easy-to-perform screening methods; VIA is a popular option. Variants of this method include VIA with magnification or with Lugol's iodine. These tests have been demonstrated to be sensitive but not specific (46). The HPV vaccine is not widely available in India at present, mainly due to its cost. A study of the willingness of parents to vaccinate their daughters was performed in Eastern India and reported that, initially, only 40% of parents agreed to vaccinate their children; this increased to 80% following a short education session about the vaccine (50). The most common reason stated for refusing the vaccine was the safety of the vaccine, followed by the perception of the vaccine as permission to engage in sexual activity (51). Effective vaccination against HPV 16 and 18 in India is expected to result in a 75% decrease in the number of cervical cancer cases (47).

The poorest regions of Latin America with the lowest resources have high rates of cervical cancer, possibly due to economic, social, educational and geographical factors that limit access to cervical cancer screening (52). Brazil is one of the few countries that have implemented an organised screening program (52). It is predicted that >8,079 women die every year in Brazil from cervical cancer (15). HPV infections have been estimated to affect >5.7% of women in Brazil and account for 68% of cervical cancer cases (53). Brazil has a long history of cervical cancer screening programs, the first of which was initiated in 1956 (54). The screening strategy for preventing cervical cancer in Brazil targets women between 25 and 64 years of age. Pap smears are recommended to be repeated every 3 years (55). However, similarly to other developing nations, there is a shortage of resources, especially in trained healthcare professionals, that limits the coverage of the population using cytology-based pap-smear screening. The physical size of the country is another factor limiting screening coverage, which is further complicated by the large population, as there are >64 million women aged >15 years in Brazil (55). To lower HPV infection rates and control the rates of cervical cancer, the National Health System of Brazil has adopted the quadrivalent HPV vaccine as part of the national vaccination program; the vaccine was adopted in 2014 and is offered to girls between 9 and 13 years of age, and to women infected with HIV between the ages of 9 and 26 years.

Several factors other than persistent HPV infection contribute to the development and/or progression of cervical cancer, including smoking tobacco (including cigarettes, cigars, pipes, hookah and shisha), high parity, continuous use of oral hormonal contraceptives, promiscuity and co-infection with HIV (Fig. 2) (1,16,56). Of those, high parity and tobacco smoking are the most important contributing factors, as they mediate HR HPV infection progression, which results in high rates of cervical pre-cancer and cancer (57–59). Chatzistamatiou et al (58) identified a significant association between smoking and HR HPV DNA positivity, but not between smoking and the viral HPV 16 E7 oncoprotein in HPV-associated carcinogenesis (58). In addition, the study displayed a higher odds ratio for smokers and ex-smokers compared with that for non-smokers (58). In contrast to non-smokers, continuous cigarette smokers have previously been reported to exhibit higher risk of developing SCC; among women with an increased smoking intensity, those who start smoking at a young age are at higher risk of developing SCC but not AC (60,61). However, Haverkos (62) observed no significant association between cervical cancer and smoking. Therefore, the influence of smoking on increasing the risk of developing cervical cancer remains controversial. However, previous studies have provided evidence of cigarette smoking derivatives acting as causative agents of cervical and lung cancer (61,63).

Co-infection with Chlamydia trachomatis and herpes simplex virus type-2, immunosuppression, and nutritional challenges have also been demonstrated to contribute to cervical cancer development and progression (1,16). Several genetic and immunological host and viral factors are also predicted as contributing factors (64). Goodson et al (65) identified >80 environmental chemicals that serve roles in dysregulating host pathways in carcinogenesis. Environmental risk factors for cervical cancer also include compounds associated with cigarette smoke, such as coal tar derivatives, tar-based vaginal sanitary products and smoke inhaled from biomass-burning stoves (62). These environmental factors can activate signalling pathways responsible for the carcinogenesis of HPV-related cancers, including SCC, in low-income countries (62). These pathways are similar to those known as the hallmarks of cancer, and include hyperproliferative signalling, insensitivity to growth-factor signals, evasion of apoptosis, continuous angiogenesis, genomic unsteadiness, mutation, advanced inflammation and the disruption of normal metabolic functions (65).

In the past decade, the World Health Organization (WHO) reported that billions of individuals from developing regions such as Africa still utilize coal, crop residue, dung and wood for heating and cooking purposes. This is unfortunate because biomass-burning stoves are universally known as a vital source of bio-carcinogens (65). Therefore, women exposed to excessive smoke from these stoves are at greater risk of developing cervical cancer (16,66). This was further verified by Bennett et al (67), who identified an association between the use of solid fuel and cervical cancer.

Coaltar derivatives, such as Lysol, are sometimes used in vaginal sanitary products. The first evidence to associate Lysol usage with cervical cancer was in 1931 when it was noted that the majority of a group of New York women with cervical cancer were continuous users of Lysol sanitizers (62). Lysol is a tar-based derivative, which was initially used in animal research for carcinogenesis (68). A later study amongst Californian women found a significant association between the use of Lysol and cervical cancer (69). Goodson et al (65) also reported that chemical constituents of tobacco (e.g. benzyl pyrenes, polycyclic aromatics and tobacco-based nitrosamines) and tar-based vaginal sanitizers could affect the development of cancer, including cervical cancer, since they penetrate cells and tissues, and stimulate vital carcinogenic pathways. The precise understanding of these pathways may lead to more effective immunotherapeutic strategies and control measures of HPV-related tumours that are usually induced in HR populations exposed to multiple carcinogens due to a low socioeconomic background.

Genetic polymorphisms are single nucleotide base changes that occur between two genomes as a deletion, insertion or a substitution of a single nucleotide. These alterations can either be insignificant due to being silent, or they can be highly significant, as they can lead to different types of disorders, such as cervical cancer (70). HPV is considered to be the primary contributory factor to cervical cancer tumour angiogenesis, although a review of previous studies (71) reported additional contributors, including the regulation of long non-coding RNAs (lncRNAs) and/or their gene polymorphisms, such as polymorphisms in toll-like receptor (TLR) genes (72).

LncRNA LINC00673 has been implicated in the development and prognosis of multiple tumours, including SCC (73). In 2018, Wang and Luo (72) demonstrated that the genetic variant of LINC00673 rs11655237 increases vulnerability to cervical cancer in the Chinese population, suggesting that this gene variant is associated with the risk of cervical cancer The study further suggested that downregulation of the transcription levels of LINC00673 rs11655237 in cervical tissues may be the main reason for the association between the genetic variant rs11655237 and the risk of cervical cancer. In addition, a G-to-A nucleotide substitution in the rs11655237 gene variant of LINC00673 may be the cause of dysregulated transcription, as it generates a target locus for microRNA (miRNA or miR)-1231 attachment, which in turn inhibits LINC00673 (60,74). The A allele and the AA/AG genotype of the rs11655237 gene variant have been demonstrated to be associated with the risk of developing cervical cancer, since the gene variant alters the transcription of LINC00673, which is vital for tumour suppression (Fig. 3) (72).

In 2018, Weng et al (75) investigated the association between the lncRNA HOX transcript antisense intergenic RNA (HOTAIR) genetic polymorphisms and the recurrence of cancer, as well as the survival rates of patients with cervical cancer. Although no significant association was observed between HOTAIR gene polymorphisms and patient clinicopathological characteristics, the study revealed that GG-genotype carriers in the HOTAIR rs920778 gene variant exhibited high risk of cervical cancer recurrence, low predicted survival due to stomal and pelvic lymph node metastasis, and increased mortality compared with carriers of the AA/AG genotype (74–76). Although the AA genotype is not associated with cervical cancer, it is significantly associated with gastric and oesophageal squamous cancer in Chinese populations (77). Therefore, the prognosis of a patient may depend on the impact of HOTAIR expression on the rs920778 gene variant. In addition, since the HOTAIR gene polymorphism rs920778 has insignificant associations with cervical cancer carcinogenesis, it cannot be described as a potential predictive factor for patient prognosis (75).

A previous meta-analysis conducted by Yang et al (78) identified an association between TLR gene polymorphisms and the risk of cervical cancer. The results revealed that white populations carrying the C allele of the TLR 9 1486 T/C gene polymorphism and the A allele of the TLR 9 G2848A gene polymorphism were significantly associated with an increased risk of developing cervical cancer (78,79). TLR 9 has been previously reported to promote cervical intraepithelial neoplasia (CIN) progression in women from Tunisia (80). These results suggested that TLR 9 may represent a potential biomarker for the malignant transformation of cervical squamous cells. The ability of genes and epigenetic factors to act as contributors of cervical cancer carcinogenesis, and the identification of these factors indicate their potential use in diagnosis and treatment.

In 2013, Adesina et al (125) estimated that 11 million women in Sub-Saharan Africa would be diagnosed with cervical cancer within the next 10–20 years, with ~1.7 million cases diagnosed in 2010 (126). Prevention of cervical cancer is regarded as the best control method; however, treatment is also an important intervention (127). A cost-effective HPV vaccine has been reported as lifesaving amongst girls between 9 and 12 years of age (50). The number of cervical cancer cases are predicted to effectively decrease after five decades of comprehensive vaccination (128). There are two types of HPV vaccines used for targeting the predominant subtypes of HPV: The bivalent vaccine, which targets the HPV 16 and 18 subtypes, and the quadrivalent vaccine, which targets the HPV 6, 11, 16 and 18 subtypes (2,129). HPV vaccines have been reported to effectively assist in preventing HPV infection, and result in the prevention of CIN (130,131) HPV vaccination first became popular in high-income countries but remained unpopular in low income countries due to the high price of the vaccine. Since 2011, HPV vaccinations have gained popularity in middle-income countries due to a decrease in cost (2); since 2012, increased financial support for HPV vaccination projects in low-income countries has enabled such countries to adopt vaccination programs (2,132). HPV vaccination for women in South Africa was first introduced in 2014 through the National HPV Immunization Program. The primary target age for HPV vaccination in South Africa is 9 years (pupils in grades 3 and 4) (6,17). According to the European Medicines Agency, the standard dose for girls <14 years of age is two doses at 0 and <6 months depending on whether they are receiving the Cervarix or Gardasil vaccine (21). Herrero et al (2,7) clinically demonstrated that three doses of HPV vaccine can provide total protection against persisting HPV infection and associated precancerous lesions in women aged between 15 and 26 years old, provided that they have not been previously exposed to the virus (7). Therefore, treatment (or vaccination) and screening is crucial for lowering the incidence, burden and mortality rates of cervical cancer (7).

It is of great global interest to eliminate or decrease the number of new cases and high mortality of cervical cancer caused by persistent HPV infection. Therefore, Pap smear screening for cervical cancer is highly encouraged during the HIV diagnosis process. This procedure should be repeated every 3 years for women who have been previously screened and diagnosed as negative (50). Regular screening for cervical cancer amongst women is predicted to lower the lifetime risk of developing the disease (133). Population screening for cervical cancer in regions of low socioeconomic status and low-resource settings remains elusive; the cervical cancer screening coverage in Southern Africa ranges between 4.1 and 38.0%. A study of 642 females in urban areas found that 17.3% had been screened, while of 580 females in rural areas 9.6% had been screened for HPV (130,134,135). This low coverage is due to factors such as inaccessibility (due to areas being remote), lack of funding, community awareness and cost-effectiveness, complications of Pap smear, a lack of public policy attention, or the implementation of ineffective public policies (128,130,136).

HIV-associated cervical cancer incidence is predicted to gradually increase in LMICs for the next 10 years (137). Despite the incidence of cervical cancer in many LMICs being lower than in many developed countries, the cancer burden in LMICs is increasing due to the advanced stage at diagnosis and inaccessible treatment (28). Thus, immediate action in the public and global health sectors is advised (2,138). Effective precancerous lesion detection using the PapilloCheck^® microarray and the HPV restriction fragment length polymorphism (RFLP) PCR assay was achieved with 62.5 and 25.0% HPV co-infection detection, respectively (4). The RFLP PCR assay is suggested as a primary HPV test for screening in LMICs, as it is cost-effective, while the PapilloCheck^® microarray assay is considered a more sensitive and descriptive test (4). However, widespread access to screening at the population level in LMICs remains challenging. For example, in Uganda, cervical cancer is the leading type of cancer amongst women, with 3,915 new cases and 2,275 deaths per year (21); however, <10% of Ugandan women have ever been screened (139).

Several studies have reported multiple compounding factors that contribute to non-participation of women in cervical cancer screening, such as unemployment, lack of or low education level, poor language proficiency (for example, the information and education campaigns not being provided in the native language of the women the programs are aimed at), being unmarried, lack of knowledge of screening, previous negative experiences of screening, cultural and traditional beliefs, and multiple other determinants (140–142). Thus, the WHO and the European Commission have recognised that equal access and equal utilization of healthcare is essential to deal with inequity issues in healthcare (143). This may improve healthcare service practices such as screening and treatment (144,145). In conclusion, appropriate cervical cancer screening programs and good-quality cytological testing can assist in lowering the incidence and mortality rates of cervical cancer. The effectiveness of prevention and treatment programs is dependent on equity in healthcare and good healthcare service practices. A lack of cervical cancer screening is not the sole cause for the high burden of cervical cancer in LMICs. Another important consideration is the decision on whether to treat a patient based on a positive result for an HPV test. Since most HPV infections clear spontaneously, especially in younger women, if a patient is treated without further screening, it may contribute to unnecessary treatment costs (146).