Changes in The Burden of HIV-Related Cervical Cancer Over A Decade in Côte d’Ivoire


 BACKGROUND: Major improvements have occurred in access to antiretroviral treatment (ART) and invasive cervical cancer (ICC) prevention of HIV-infected women over the past decade in sub-Saharan Africa. However, there is limited information on changes in the burden of HIV-related ICC at a population level. Our objective was to compare HIV-related ICC over a decade and document factors associate with HIV infection in women with ICC in Côte d’Ivoire.METHODS: A repeated cross-sectional study was conducted in referral hospitals of Abidjan, Côte d’Ivoire during the 2009-2011 and 2018-2020 periods. During both periods, women diagnosed with ICC were systematically tested for HIV. A common questionnaire was administered to collect demographic information, ICC risk factors, cancer stage (FIGO) and HIV characteristics (ART use, last known CD4 count) for those screened positive. Characteristics of HIV-related ICC were compared between the time periods and factors associated with HIV in women diagnosed with ICC in 2018-2020 were documented through a multivariate logistic model.RESULTS: During the 2009-2011 and 2018-2020 periods, 147 and 297 women with ICC were diagnosed, with median [IQR] age at ICC diagnosis of 49 [40-57] years and 51 [43-60] years (p=0.01), respectively. The estimated HIV prevalence was 24.5% and 21.9% (p=0.53), respectively. An advanced FIGO stage (III, IV) was documented in 74.5% and 76.2% of women during these two time periods (p=0.72). In HIV-infected women, access to ART increased from to 2.8% to 73.8% (p<10-4) and median CD4 cell count from 285 [IQR 250 – 441] to 492 [IQR 377 – 833] cells/mm3 (p=0.03) between the two time periods. In Women diagnosed with ICC during the 2018-2020 period, HIV infection was associated with a less advanced clinical stage (FIGO I/II stage) [aOR=2.2 (95%CI 1.1-4.4)] and with higher ICC diagnosis through a systematic screening [aOR=10.5 (95%CI 2.5-45.5)].CONCLUSIONS: Despite an improved access to ART in Côte d’Ivoire, the proportion of HIV-infected women diagnosed with ICC remains high in 2020. HIV-infected women diagnosed with ICC in 2018-2020 presented with less advanced stage and a higher access to ICC screening at diagnosis compared to their uninfected counterparts suggesting an enhanced access to early ICC diagnosis.

SSA, its impact on the risk of ICC remains unclear [6][7][8]. However, a recent meta-analysis suggested a protective effect of ART on the risk of cervical precancerous lesions and ICC [9]. As ART continues to expand in SSA, more evidences are needed to characterize its potential impact on the subsequent risk of AIDS-de ning malignancy such as ICC in HIV-infected women.
During the last decade, a growing number of ICC screening programs have been piloted or/and implemented in SSA, many of them partly or fully conducted through integrated HIV care services [10,11].
In Côte d'Ivoire, pilot programs initially targeting HIV-infected women have been progressively extended to none HIV healthcare facilities [12][13][14]. However, there is limited information on how improved access to HIV prevention and care services combined with the increased access to ICC screening may have in uenced the characteristics of HIV-related ICC. Our objective was to compare the characteristics of HIV- from the three public referral hospitals were involved as previously reported in a rst large case-referent study on Cancer and HIV conducted in West Africa [3]. The 2018-2020 period covered all wards potentially managing ICC from the public and private sector in the urban area of Abidjan.

Collected information
Women enrolled during the two time periods were administered a similar structured questionnaire to collect socio-demographic characteristics including age, formal education (categorized as no school, primary school, secondary school and over), personal monthly income, age at rst sexual intercourse, parity, tobacco use (categorized s current or former tobacco use versus never users) and current hormonal contraceptive use. Cancer clinical stage at ICC diagnosis was assessed based on the International federation of gynaecology and obstetrics (FIGO) staging system [15]. Based on available information after the initial assessment of the tumour extension, clinical stage at diagnosis was reported by clinicians and dichotomised as early (stage I and II) or advanced (stage III and IV) disease.
Additional information was collected during the 2018-2020 period including the existence of any personal health insurance coverage. Pre-diagnosis history was also documented including date of rst reported ICC-related symptoms, date of rst consultation at an ICC referral centre, whether ICC was diagnosed following attendance to a systematic ICC screening without prior symptoms or not and attendance to a traditional healer or using any traditional treatment for ICC-related symptoms prior to diagnosis.  [16]. Unlike ten years ago, the majority of HIV-infected women diagnosed with ICC in 2018-2020 where aware of their HIV status and currently on ART. Women diagnosed with ICC in the 2018-2020 harbored signi cantly higher CD4 count measures compared to women diagnosed through the 2009-2011 period. However, despite these major improvements in access to care and ART use among HIV-infected women, the proportion of women diagnosed with ICC and infected with HIV remained high and stable over time. A previous meta-analysis has suggested that access to ART and immune restoration have a protective effect on the occurrence of ICC in HIV-infected women [9]. Although our study was not designed to assess the impact of access to ART on the occurrence of ICC, a protective effect of ART should ultimately translate into a decrease in the attributable fraction of HIV in ICC and therefore, in a decrease of the subsequent proportion of HIV-related ICC. In Southern Africa, a cohort analysis documenting the incidence of ICC among 10,640 HIV-infected women followed for a median time after ART initiation of 2.1 years (IQR 0.7-4.1 years) did not observe any decline in ICC incidence rates by time since ART initiation [17]. While ART might confer a certain amount of prevention against ICC, growing evidence suggest that this will not translate into a major decrease in the burden of ICC in HIV-infected women before many years. It is therefore, essential to increase the support of ICC screening programs integrated in HIV clinics as these women remained particularly at-risk despite ART use and immune restauration.
Tobacco and hormonal contraceptive use increased over time regardless of HIV status in Côte d'Ivoire.
Exposure to smoked or chewed tobacco as well as prolonged exposure to hormonal contraceptive use have shown to increase the risk of premalignant cervical lesions and ICC [18,19]. Women in Côte d'Ivoire, as in many resource-constraint settings are increasingly confronted to a double burden of traditional ICC risk factors including high exposure to oncogenic human papillomaviruses combined with a growing exposure to western lifestyle risk factors such as tobacco use. Prevention programs implementing ICC screening through healthcare facilities such as HIV clinics should be aware of these changes. This could be particularly relevant for tobacco use which has shown to be higher in HIV-infected people even in low income countries [20]. Preventive approaches against tobacco use could be considered in combination with ICC screening through prevention messages and targeted smoking cessation programs for active tobacco users.
During the 2018-2020 period, and unlike the 2009-2011 period, HIV-infected women diagnosed with ICC were less likely to present with an advanced clinical stage compared to their HIV-uninfected counterparts. In addition, during the 2018-2020 period, HIV-infected women were more likely to access ICC diagnosis through a systematic screening. These ndings suggest an improved access to ICC preventive and care services for HIV-infected women. Indeed, HIV-infected women diagnosed with ICC are now mainly known to be HIV infected and regularly followed up for their HIV disease providing more opportunities in their access to care for other conditions including malignancies. In Côte d'Ivoire, ICC screening programs have been initially implemented in HIV clinics before being extended to other healthcare facilities. These arguments might explain the enhanced access to ICC care among HIV-infected women. However, results from previous studies on the association between ICC clinical stage and HIV status are con icting. A previous study conducted in women diagnosed with ICC during the 2008-2012 period in a referral hospital in Ethiopia reported an almost 1.5 times increased risk of diagnosis at a more advanced stage in HIVinfected women compared to HIV-negative women [21]. Alternatively, Menon et al reported a similar association between early clinical stage and HIV infection in 315 women diagnosed with ICC between 2003 and 2010 in Uganda [22]. Both studies were conducted in women diagnosed with ICC many years ago, when HIV care and ICC screening were clearly less available than nowadays; It is therefore important to provide more recent estimates of this association between HIV infection and ICC stage from other settings in SSA.

Limitations
The cross-sectional nature of the study prevents from drawing any inferential relationship between HIV infection and its impact on the incidence of ICC over time. Indeed, the impact of HIV infection on the burden of cancers usually relies on cohort study design and record linkage studies with data extracted from population-based cancer registries. However, in most resource-limited settings, challenges associated with the documentation and continuous recording of cancers over time prevent from conducting these longitudinal approaches. Alternatively, the replication of cross sectional studies over time using similar methods in the same catchment area enables the documentation of potential evolution in cancer characteristics providing informative and useful data to clinicians and decision makers. Due to limited available data, our de nition of an advanced stage at diagnosed did not followed the standard de nition used for eligibility to a curative surgery (stage I, IIa versus stage IIb, III/IV). Therefore, the reported difference in the proportion of advanced clinical stage might not re ect a difference in access to curative treatment and ultimately enhanced survival.
Our study population might not re ect the exact distribution of ICC occurring in Côte d'Ivoire. However, the urban area of Abidjan remains the only location providing treatment for ICC in the country as well as the great majority of pathology units able to diagnose ICC. While a few diagnoses might be reported outside this catchment area, women diagnosed with ICC should be ultimately referred to one of these referral centers.

Conclusion
Characteristics of HIV-related ICC have signi cantly evolved over the last ten years with now most HIVinfected women already on care and presenting with less advanced HIV disease. These achievements towards HIV care did not translate into a reduced burden of HIV infection in women presenting with ICC between 2018 and 2020 in Côte d'Ivoire. However, HIV-infected women presented with a lower proportion of advanced ICC. This nding supports the need to continue and expand ICC screening services into preexisting healthcare facilities such as HIV clinics or family planning centers. Will this greater access to early ICC diagnosis translates into better survival in HIV-infected women remains to be determined.

Declarations
Ethics approval and consent to participate: All women enrolled in 2009-2011 and 2018-2020 provided their informed and written consent prior to participate. The study was approved by the national ethic committee of Côte d'Ivoire [n°011-19/MSHP/CNESVS-kp].