Cervical cancer screening in HIV-endemic countries: An urgent call for guideline change

Abstract

Women living with HIV (WLWH) are at an increased risk of developing HPV-related high grade cervical dysplasia and cervical cancer. Prior World Health Organization (WHO) screening guidelines recommended starting screening at age 30. We assessed characteristics of women diagnosed with cervical cancer to further inform and refine screening guidelines. We prospectively enrolled women diagnosed with cervical cancer from January 2015 to March 2020 at two tertiary hospitals in Gaborone, Botswana. We performed chi-square and ANOVA analyses to evaluate the association between age upon diagnosis and HIV status, CD4 count, viral load, and other sociodemographic and clinical factors. Data were available for 1130 women who were diagnosed with cervical cancer and 69.3% were WLWH. The median age overall was 47.9 (IQR 41.2–59.1), 44.6 IQR: 39.8 – 50.9) among WLWH, and 61.2 (IQR 48.6–69.3) among women living without HIV. There were 1.3% of women aged <30 years old, 19.1% were 30–39 and 37.2% were 40–49. Overall, 20.4% (n = 231) of cancers were in women <40 years. Age of cervical cancer diagnosis is younger in countries with higher HIV prevalence, like Botswana. Approximately 20% of the patients presented with cancer at <40 years of age and would have likely benefited from screening 10 years prior to cancer diagnosis to provide an opportunity for detection and treatment of pre-invasive disease.

Introduction

Women living with the human immunodeficiency virus (WLWH) are at an increased risk of acquiring human papilloma-virus (HPV) related high-grade cervical dysplasia that can progress to cervical cancer [1]. In sub-Saharan Africa, cervical cancer contributes the largest proportion of years of life lost due to cancer, in large part due to women diagnosed at younger ages [2]. Prior World Health Organization (WHO) guidelines for cervical cancer screening recommend initiation at age 30 [3]. Within our Multidisciplinary Clinic in Botswana, that sees the majority of diagnosed cervical cancers in the southern part of the country, we aimed to evaluate the age of diagnosis of new cervical cancers [4].

Recently updated WHO guidelines, recognizing the excess risk among immunocompromised individuals, support lowering the age of initiation of screening to 25 years in WLWH. The newly updated cervical cancer screening guidelines, published in July 2021, also recommended testing at shorter intervals for WLWH (3–5 years) when compared to the general population (every 5–10 years) [5].

Given the natural history of cervical cancer and progression from persistent infection to dysplasia and ultimately invasive cancer, women diagnosed between 35 and 50 years have a window of opportunity for early diagnosis and treatment to prevent development of cervical cancer and impede the progression to invasive disease [4]. The guidelines note that this was a conditional recommendation, with low-certainty evidence, in need of further data to strengthen their recommendation.

To further support the WHO guideline change, we present data of a prospectively enrolled cohort of patients diagnosed with cervical cancer in Botswana. Botswana is a middle-income country in sub-Saharan Africa, where cervical cancer is the leading cancer in females. The HIV burden disproportionately impacts women and HIV prevalence among females >15 years of age in Botswana is reported at 59% [6]. Given the high rate of HIV-infection in this population, our aim of this study was to assess characteristics of women diagnosed with cervical cancer in Botswana at a time when prior WHO cervical cancer screening guidelines were being used to inform and support screening recommendations.

Methods

This cross sectional study included women diagnosed with cervical cancer from January 2015 to March 2020 at Princess Marina Hospital and Gaborone Private Hospital in Gaborone, Botswana as part of our Botswana Cancer Cohort. These hospitals provide oncology care for the majority of patients in southern Botswana. Inclusion criteria were women who were at least 18 years old and presented to the hospital for initial cancer treatment with a pathologically confirmed diagnosis of cervical cancer. HIV information was collected at the time of cancer diagnosis by patient self-report. For WLWH, most recent CD4 count and viral load data were collected based on most recently available medical charts and lab data. ARV information including start of treatment and current regimen were collected. For women living without HIV, last testing date was collected, and if >6 months prior, retesting was recommended. We performed chi-square and ANOVA analyses to evaluate the association between age at diagnosis and HIV status, CD4 count, viral load, and other sociodemographic and clinical factors.

Results

Data were available for 1130 women, with 69.3% being WLWH. Of these women (median age 47.9 (IQR 41.2–59.1)), 1.3% were <30 years old, 19.1% were 30–39, 37.2% were 40–49 and 42.4% were ≥50. Overall, 20.4% (n = 231) of cancers were in women <40 years. The most common age range of diagnosis for invasive cervical cancer was 35–44 years of age in WLWH vs. 65–74 years of age in women without HIV (Fig. 1). Mean CD4 counts and viral load were similar for WLWH <40 years (655.10 cells/μL and 18.2% with a detectable viral load), and for WLWH ≥40 years (619.58 cells/μL and 23.8% with a detectable viral load). CD4 count and viral load information were collected at the time of cancer diagnosis. Demographic data on this cohort has been previously published [7]. CD4 count was available for 83% of WLWH and viral load was available for 24% of the population. Importantly, over 90% of the population was on anti-retroviral therapy [7]. Nearly half (46%) of the women <40 years presented with FIGO stage III/IV cancer. Women <40 years were more likely to have been screened for cervical cancer at least once compared to women ≥40 years (59.1% vs 50.7%, p = 0.03), although it is important to note that most of these women presented to screening with symptoms consistent with invasive cancer. The majority of women with a history of prior screening for cervical cancer in both age groups were WLWH (87.4% <40 years and 70.5% ≥40 years). Table 1

Fig. 1.

Proportion of cervical cancer cases by age and HIV status.

Table 1.

Clinical data for patients diagnosed with cervical cancer.

	<40 years of age	40+ years of age	p-value*
	N = 231 (20.4%)	N = 900 (79.6%)
HIV status	<0.001
HIV negative	32 (9.4%)	309 (90.6%)
HIV positive	199 (25.8%)	571 (74.1%)
Missing	0 (0.0%)	20 (100%)
Stage	0.08
I	29 (16.1%)	151 (83.9%)
II	85 (23.7%)	274 (76.3%)
III	75 (18.8%)	325 (81.3%)
IV	23 (26.1%)	65 (73.9%)
Missing	19 (18.3%)	85 (81.7%)
Mean CD4 Count (SD)	655.1071 (1310.593)	619.5806 (1093.361)	0.73
Viral load (n = 185)	0.4
Undetectable	45 (31.3%)	99 (68.8%)
Detectable	10 (24.4%)	31 (75.6%)
Screening History	0.028
Never	88 (17.2%)	425 (82.8%)
Ever	127 (22.5%)	437 (77.5%)
Missing	16 (29.6%)	38 (70.4%)

Discussion

Our data support that age of cervical cancer diagnosis may be younger in countries with higher HIV prevalence, particularly among WLWH. With 42.4% of women diagnosed over the age of 50, there is still consideration for screening in an older population. Further, advanced stage of presentation among women <40 suggests that cancer likely developed several years prior to presentation, critically underlying the need for guidelines to include younger women in screening, especially WLWH. Approximately 20% of all patients who presented with cancer were <40 years and would probably have benefited from screening at least 10 years before cancer diagnosis to potentially prevent cancer from ever developing. However, these patients would not have been eligible for screening per the prior WHO screening guidelines (in effect from 2013 to June 2021). Similarly, a recent retrospective study from the region looked at screening outcomes among over 5000 women screened for cervical cancer utilizing visual inspection with acetic acid (VIA) in a clinic mainly serving WLWH [6]. Eighteen percent of the women screened were 25–29 years old and 90% of all women were WLWH. Importantly, among all women screened, those that were VIA+ were more likely to be younger and living with HIV. WLWH aged 25–29 years had the same odds of having histologically confirmed high grade cervical dysplasia as WLWH in the age group 30–49 years old. This screening data supports the earlier development of cervical dysplasia in WLWH. Previously published studies have demonstrated significantly higher rates of VIA positivity among WLWH as compared to the general population cohorts across the region (40% vs 20% in Zambia, 14% vs 5% in South Africa, 12% vs. 3% in Tanzania, 8% vs 2% in Cote d’Ivoire, and 17 vs 15% in Namibia) [8–13]. While this data increases the information regarding age of diagnosis among WLWH and cervical cancer in Sub-Saharan Africa, we recognize the limitations of our study. This is a large cross-sectional study with over 90% of women on antiretroviral therapy. There is missingness in our data regarding viral load (>70% missing); however, CD4 count data and ARV data are largely complete (>80% confirmed). Our data further demonstrate that invasive cervical disease develops at a younger age in WLWH and that with earlier screening, pre-invasive lesions could be identified.

Conclusion

This study provides further support for the change of international cervical cancer screening guidelines to include women at younger ages than 30–49 years, especially in areas with high prevalence of HIV and particularly for WLWH.

Additionally, our data demonstrate that WLWH have higher screening rates than the general population, possibly due to more frequent contact with the health care system. The reduced age of initiation for screening in this population would likely identify high-grade cervical dysplasia earlier, allowing opportunities for treatment and thus contribute to reduced rates of invasive cervical cancer disease in the future.