Cervical cancer is the fourth leading cause of cancer death in women worldwide and the leading cause of cancer death in women in Botswana.1–3 The disease burden in Botswana is affected by the high prevalence of human immunodeficiency virus (HIV), which is 22% among people aged 15–49 years and is a well-established risk factor for cervical cancer.4–6 Most cervical cancers are associated with infection with high-risk human papillomavirus (HPV) types.7–9 Globally, HPV prevalence is variable, ranging from 15–45%, with higher prevalence in women living with HIV.10–12 Human papillomavirus 16, 18, and 45 are the high-risk types most commonly associated with cervical cancer in Africa.13–15 Among women living with HIV, persistent high-risk HPV positivity and infection with multiple types are strong risk factors for cervical cancer.16
Cervical cancer is largely preventable and treatable where screening and treatment programs are available.17–20 Cervical cancer screening strategies are most effective when based on local evidence and tailored to the population and resource infrastructure.21 Current National Cervical Cancer Prevention Programme guidelines in Botswana use a combination of cytology (Pap test) and visual inspection with acetic acid. However, there is mounting evidence that primary high-risk HPV testing is the most effective screening strategy because of its high sensitivity (95%).22 High-risk HPV testing is increasingly included in some national guidelines.23–25 High-risk HPV testing is planned for the next 5-year National Cervical Cancer Prevention Programme guidelines in Botswana, but the guidelines for managing positive high-risk HPV results remain unclear, particularly among women living with HIV.26–28 Appropriate triage of a positive high-risk HPV result is necessary to prevent overtreatment of high-risk HPV when it is associated with no or low-grade cervical dysplasia. The best two-stage screening strategy is unknown for women living with HIV in resource-limited settings.29–30
In this study, we investigated the performance of primary high-risk HPV testing followed by cytology, visual inspection with acetic acid, and colposcopy to predict preinvasive cervical disease in women living with HIV in Botswana. We hypothesized that visual inspection with acetic acid, cytology, and colposcopy would perform similarly as a triage test in women living with HIV who test positive for high-risk HPV. Evaluating cervical cancer screening algorithms with primary high-risk HPV testing in women living with HIV is essential for establishing an evidence-based screening strategy in this high-risk population.
We conducted a prospective cohort study of women seeking care at the infectious disease care clinic at Princess Marina Hospital, the regional tertiary referral hospital in Gaborone, Botswana. Women included in the study were HIV-positive, older than 24 years of age, and competent to understand study procedures and give informed consent. Women were excluded if they were currently pregnant, currently menstruating heavily or with persistent vaginal discharge, had a previous hysterectomy, or had a previous diagnosis of cervical cancer.
Eligible women were provided study information by a research assistant or study nurse and offered voluntary participation while waiting for their scheduled clinical visit. After obtaining informed consent, we administered a questionnaire including demographic data, HIV treatment history, history of cervical cancer screening, and knowledge about cervical cancer. In addition to patient report, the electronic medical record was searched for results of prior cervical cancer screening. The institutional review boards of the Botswana Ministry of Health and Wellness, the University of Botswana, and the Beth Israel Deaconess Medical Center approved this study. The ethics committee of Princess Marina Hospital also approved this study. The study was registered at ClinicalTrials.gov, NCT03324009.
All participants underwent a speculum examination of the cervix by a trained study nurse, at which time samples were collected from the cervix for high-risk HPV testing and for cervical cytology using a Cervex-brush. Human papillomavirus specimens were placed in a PreservCyt transport medium, and testing was performed using the Xpert HPV Assay at the Botswana Harvard AIDS Initiative Partnership Laboratory. The Xpert HPV assay tests for 14 high-risk HPV types, including 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68. Cytology was prepared by spreading collected cervical cells from a Cervex-brush onto a glass slide and fixing with a spray fixative at the collection site. Cytology was sent to the National Health Laboratory for processing and pathologist evaluation and reported using the revised Bethesda classification.31 Abnormal lower genital tract cytology was evaluated at two thresholds: atypical squamous cells of undetermined significance (ASC-US) or worse and high-grade squamous intraepithelial lesions (HSIL) or worse.
To ensure that all participants underwent cervical cancer screening according to the standard of current guidelines in Botswana, we also collected cytology at the time of high-risk HPV sample collection. At the time of the study, there were no national clinical guidelines for management of positive high-risk HPV test results. We referred participants who tested negative for high-risk HPV to colposcopy if they had a study cytology of HSIL or had a prior abnormal cytology result and study cytology result of ASC-US or worse in accordance with current Botswana National Cervical Cancer Prevention Programme algorithms. We referred all participants who tested positive for any high-risk HPV type to visual inspection with acetic acid and colposcopy, regardless of their cytology result. The cytology result from the initial specimen collection was used for the evaluation of the two-stage screening algorithm of high-risk HPV testing followed by cytology. At the time of the colposcopy visit, participants underwent a speculum examination of the cervix, with both visual inspection with acetic acid and colposcopy performed by health care providers who were blinded to the HPV test results and cytology results. Visual inspection with acetic acid was performed by a trained nurse midwife who had participated in the Botswana Ministry of Health and Wellness national visual inspection with acetic acid training program and was experienced in performing visual inspection with acetic acid in the clinical setting. Visual assessment was performed after applying 5% acetic acid to the cervix using a cotton swab, and findings were categorized as normal, abnormal with recommendation for cryotherapy, or abnormal with recommendation for loop electrosurgical excision procedure (LEEP). In the analysis, we considered lesions recommended for cryotherapy as “low-grade” and lesions recommended for LEEP as “high-grade.” Subsequently, a gynecologist blinded to the visual inspection with acetic acid assessment performed colposcopy, and normal, low-grade, or high-grade impression was recorded. All participants had a biopsy collected at the time of colposcopy. If there was a visible lesion, a punch biopsy or LEEP was performed according to current best practice in Botswana. If no lesion was visible, a small endocervical excision or an endocervical curettage was performed. All women with cervical intraepithelial neoplasia (CIN) 2 or higher on biopsy or endocervical curettage were referred for an excisional procedure. Women with histopathology showing CIN 3 with microinvasion or invasive cervical cancer were referred to gynecologic health care providers for further assessment and treatment.
The primary outcome was performance of two-stage cervical cancer screening algorithms in detecting high-grade cervical dysplasia. We defined high-grade cervical dysplasia as a colposcopy result of CIN 2 or higher. Using histopathology collected at time of colposcopy as the gold standard, we calculated the sensitivity, specificity, positive predictive value (PPV), negative predictive value, and likelihood ratios (LRs) to detect high-grade cervical dysplasia for 1) cytology after a positive high-risk HPV test result, 2) visual inspection with acetic acid impression after a positive high-risk HPV test result, and 3) colposcopy impression after a positive high-risk HPV test result. For each two-stage screening strategy, we evaluated test performance at two cutoffs. For cytology, we evaluated cutoffs of ASC-US and HSIL. For visual inspection with acetic acid and colposcopy, we evaluated cutoffs of low-grade and high-grade impressions. In addition, we repeated this analysis stratified by high-risk HPV type (16/18/45 and other high-risk HPV).
Data were entered into a REDCap electronic database by a designated research assistant, and accuracy of data entry was verified by the study nurse and principal investigator. Descriptive statistics are presented as median with interquartile range or proportion. We compared categorical variables with the χ2 or Fisher exact test and continuous variables with the Wilcoxon rank sum test. We considered two-sided P<.05 statistically significant and used SAS 9.4 for analyses.
The goal of a two-stage algorithm to detect high-grade cervical dysplasia is to increase PPV while maintaining sensitivity and specificity. In a prior cervical cancer screening study among a population of women with a relatively high HIV prevalence, the PPV of a high-risk HPV-positive test result for high-grade cervical dysplasia was 24%.28 Our sample size calculation was targeted to detect an improvement in PPV from 24% for high-risk HPV testing alone to 49% for the two-stage algorithms. Assuming a two-sided alpha of 0.05, a sample size of 81 participants with high-risk HPV was needed to yield 80% power to detect the specified difference. Based on preliminary data from a recent study of women living with HIV in Botswana, we assumed high-risk HPV-positivity would be 30% (unpublished data). Thus, we needed to enroll 270 participants with HIV to yield 81 who would be positive for high-risk HPV. To allow for 10% loss to follow-up between the primary high-risk HPV testing and colposcopy, we aimed to enroll at least 300 participants.
We recruited participants from April to July 2018, and all follow-up colposcopy visits were completed by August 2018. Of the 312 women living with HIV enrolled, 12 were lost to follow-up, deemed ineligible, or withdrew before cervical samples were collected at the first study visit, leaving 300 (96%) women who underwent high-risk HPV testing and cytology collection. Of those participants, 88 (29%) had a positive high-risk HPV result. Among those 88 who tested positive for high-risk HPV, we did not have colposcopy results for six (three were lost to follow-up, one withdrew, one became ineligible owing to pregnancy, and one biopsy specimen was lost in the laboratory); we had histopathology results from colposcopy for 82 women for this analysis. Additionally, two participants who tested negative for high-risk HPV underwent colposcopy for cytology of HSIL (Fig. 1).
Baseline characteristics were similar among women who tested positive and negative for high-risk HPV (Table 1). The majority of women reported having undergone prior cervical cancer screening (95%). There were no differences between groups in prior abnormal screening results or cervical excisional procedures. Only five women had a recent CD4 count of less than 200/microliter, and all of the participants were taking antiretroviral therapy. Only two women reported a history of smoking, and both tested negative for all high-risk HPV types.
Of the 88 (29%) women who tested positive for any high-risk HPV type, 15 of the 300 screened had HPV 16 (prevalence 5%), 21 of the 300 screened had HPV 18/45 (prevalence 7%), and 66 of the 300 screened had other high-risk HPV types (prevalence 22%). Among the 82 women with positive high-risk HPV test results who had histopathology results, 29 (35%) had CIN 2 or higher (Table 2). The prevalence of CIN 2 or higher by high-risk HPV type was 31%, 21%, and 43% for HPV 16, HPV 18/45, and other high-risk HPV types, respectively. Among the 11 participants coinfected with multiple high-risk HPV types, the prevalence of CIN 2 or higher was 45%.
We compared the performance of the two-stage cervical cancer screening algorithms. High-risk HPV followed by colposcopy impression had a sensitivity of 83%, specificity of 49%, PPV of 47%, LR+ of +1.6, and LR− of −0.4. High-risk HPV testing followed by visual inspection with acetic acid resulted in a reduced sensitivity of 59%, specificity of 49%, PPV of 39%, LR+ of +1.2, and LR− of −0.8 at the low cutoff point of “low-grade impression.” High-risk HPV testing followed by cytology also resulted in a reduced sensitivity of 62%, specificity of 77%, PPV of 60%, LR+ of +2.7, and LR− of −0.5 at the ASC-US threshold (Table 3). Triaging women who tested positive for high-risk HPV women with colposcopy impression, visual inspection with acetic acid, and cytology missed CIN 2 or higher diagnoses in 5, 12, and 11 women in our cohort, respectively. Evaluation of the two-stage algorithms stratified by HPV 16/18/45 compared with other high-risk HPV types did not improve the performance of any algorithm (Table 4).
Four women had histopathology results of cancer or microinvasive CIN 3. One of these women had HPV18/45, and the other three had other high-risk HPV types. All four had a cytology result of HSIL. Three had low-grade impressions on both visual inspection with acetic acid and colposcopy, and one had a high-grade impression on both visual inspection with acetic acid and colposcopy.
Primary high-risk HPV testing followed by colposcopy was the most sensitive two-stage algorithm for cervical cancer screening among women living with HIV in Botswana. Both visual inspection with acetic acid and cytology as second-stage screening methods had unacceptably low sensitivity, missing approximately one third of women with high-grade cervical lesions. Triaging high-risk HPV-positive results with visual inspection with acetic acid or cytology eliminated the benefit of the high sensitivity that primary high-risk HPV testing provides. Further, triaging high-risk HPV-positive results based on type did not improve the performance of any two-stage algorithm.
One third of women in our study with positive high-risk HPV primary screening results had high-grade cervical disease, which is a higher proportion than found in other populations living with HIV.32 Our population also had a higher prevalence of high-grade dysplasia among women with other high-risk HPV compared with women with HPV 16 or 18/45. This is consistent with prior studies in Botswana that showed heterogeneous HPV types associated with high-grade precancerous cervical lesions among women living with HIV (16, 18, 35, 58, and 61) and a lower prevalence of HPV 16 and 18 positivity in cervical cancer specimens.33–35 These cross-sectional data do not support triaging strategies based on high-risk HPV type, which may be considered in other African settings.36
Primary high-risk HPV testing followed by colposcopy results in a high number of referrals for colposcopy, presenting challenges in resource-limited settings.22 Guidelines for low- and middle-income countries have presumed that scaling up colposcopy is not feasible.37,38 Recent trends in cervical cancer screening in the region have focused on visual inspection strategies as opposed to colposcopy training.39 However, consideration of available data to plan effective screening programs is vital. Our findings support concerns raised in prior studies that visual inspection with acetic acid and cytology triaging of women with high-risk HPV may have variable or low sensitivity, particularly in women living with HIV, and that referral to colposcopy may be a better alternative.40–43 Building on the infrastructure that visual inspection has developed may facilitate roll-out of colposcopy, if coupled with the training of nurses and general practice health care providers in the region. In Botswana, for instance, the visual inspection with acetic acid programming has equipped a number of facilities with the capability to perform LEEP, and many LEEP sites have colposcopes not currently in use. If rapid high-risk HPV testing were available in the future, same-day triage with colposcopy and treatment at these sites would be feasible.
This study highlights the acute need to improve screening for cervical cancer and raises concern about the frequency of screening in women living with HIV in low- and middle-income countries. Current national strategy in Botswana recommends screening with cytology or visual inspection with acetic acid in women living with HIV every 3 years. Although many of the participants had been screened before (more than 90%), only 11% reported a prior abnormal result and 2–3% reported a prior excisional procedure. Our high prevalence of high-grade preinvasive cervical disease supports the need for frequent screening to ensure diagnosis of disease before progression to malignancy. In addition to high rates of preinvasive cervical disease, the rate of detection of cervical cancer in our screening cohort was relatively high at 2%. This included three women enrolled but immediately referred for suspicion for clinical stage IB cervical cancer on examination and four women with histopathology concerning for stage IA cervical cancer (cervical cancer or microinvasive CIN 3). This rate was similar to another screening cohort in Zambia, in which 6 of 200 (3%) women living with HIV had invasive cervical cancers detected at the time of screening, but was higher than other settings.44 In a large cervical cancer screening cohort of 79,506 women in India, 238 (0.3%) invasive cervical cancers were detected.25 In a cervical cancer screening cohort of 1,128 women living with HIV in India, five (0.4%) invasive cervical cancers were detected.45
We found lower rates of high-risk HPV prevalence among women living with HIV than reported in the literature, which may highlight the improvement in HIV management over time with higher antiretroviral therapy utilization and viral suppression.46,47 Botswana has had continuous access to antiretroviral therapy in the public sector since 2002, with initiation of antiretroviral therapy at graduated CD4 counts over time (initially 200, then 350) until a test-and-treat policy was initiated in 2016. Demographic differences in study populations may also contribute to this difference. Our study had a higher median age than studies conducted in the United States, Kenya, and Brazil. Additionally, the population in New York had higher risk behaviors, as indicated by high rates of smoking and ongoing intravenous drug use.48 The study population in Brazil was pregnant, which may have resulted in increased immunosuppression and higher high-risk HPV detection rates.49 Rates of high-risk HPV prevalence among women living with HIV in the region generally range from 47–57%; however, the prevalence is lower in women aged 40–49 years.50,51 In a similarly-aged cohort of women in Zambia, where 90% of participants were taking antiretroviral therapy and only 77% were virally suppressed, high-risk HPV positivity was 47%.44 Ongoing evaluation of high-risk HPV rates in women living with HIV in the modern antiretroviral therapy era are necessary to understand whether our findings are generalizable.
Our study has limitations. Our CIs are wide around sensitivity, specificity, PPV, and negative predictive value as a result of our relatively small sample size. Further research in larger populations will help to clarify whether the difference in performance detected in this study is significant. The cohort was recruited from an HIV treatment center, which may represent a unique population of health-seeking individuals and may not be representative of a broader population. Ease of communication and follow-up of abnormal results may not, therefore, be replicated in a larger population. However, we found that many women were not only reachable, but proactively followed-up their results, indicating that improved education about cervical cancer may reduce loss to follow-up and maximize dissemination of results. Although the goal of this study was to evaluate screening algorithms that would be possible with pathology services currently available, external validation of cytology and histopathology specimens was not performed, and, thus, accuracy compared with an expert gynecologic cytopathologist and pathologist was not evaluated. History of cervical cancer screening is primarily self-reported, with limited ability to confirm results in the electronic medical record. With regard to study design, the effect of coinfection with multiple high-risk HPV types could not be assessed because the study sample was not sufficiently powered for this subgroup. Finally, one visual inspection with acetic acid nurse and colposcopist conducted the evaluations; therefore, performance of these tests may not be generalizable.
Follow-up of this cohort is currently underway to evaluate the best interval and modality for longitudinal screening. Further research on the performance of technology-based cervical cancer screening methods compared with currently available methods in low- and middle-income countries is also being planned in a larger population. Balancing the cost of these strategies with clinical effectiveness is essential, and a cost-effectiveness evaluation of these strategies in Botswana is being explored. Finally, regional adoption of a test-and-treat policy for HIV may continue to affect cervical cancer rates in the long-term, because long-standing antiretroviral therapy use and initiation of treatment at higher CD4 levels may reduce the incidence of cervical dysplasia and the progression of dysplasia and increase the likelihood of CIN regression.52 Ongoing research in our population living with HIV is essential to understand this effect.
Authors' Data Sharing Statement
- Will individual participant data be available (including data dictionaries)? Yes.
- What data in particular will be shared? De-identified demographic and test result data.
- What other documents will be available? Not applicable.
- When will data be available (start and end dates)? At the termination of the follow-up study.
- By what access criteria will data be shared (including with whom, for what types of analyses, and by what mechanism)? Proposals should be directed to[email protected]. To gain access, data requestors will need to sign a data access agreement.
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