Purpose of the document
This document provides an overview of seven product categories classified as recommended for the screening, diagnosis, and treatment of precancerous lesions, and their technical specifications to aid in the selection, procurement, and quality assurance of these products for the prevention of invasive cervical cancer. These product categories were selected as the primary products to facilitate the screen-and-treat paradigm, and that are suitable for the use scenarios and climates in low resource settings (LRS). Recognizing the need to increase the quality, accessibility and availability of “screen and treat” commodities and devices in LRS, this document highlights the minimum performance, operational, and quality requirements for: HPV NAT IVDs; acetic acid for VIA; colposcopes; thermal ablation; cryotherapy ESUs for LLETZ, as well as vaginal specula.
Background on cervical cancer and treatment of precancerous lesions
Persistent infection of the cervix with “high risk” genotypes of human papillomavirus (HPV) is the major cause of precancerous lesions, which can lead to invasive cervical cancer if they are not treated. According to GLOBOCAN 2018, 311,000 women die of cervical cancer annually, 85 percent of them in low- and middle-income regions of the world. Progression to cancer usually takes many years, which gives clinicians an opportunity for early detection and time to treat lesions when they are found during screening. Incidence of cervical cancer can be seen in figure 3, developed by IARC.
HPV as the causative agent of cervical cancer HPV is currently the most common sexually transmitted infection and it is estimated that 80% of women will be infected with HPV at some point in their lifetime. Most HPV infections are transient and will clear spontaneously without any long-term consequences. However, the persistence of high-risk HPV infection is a significant risk factor in progression to cervical cancer. HPV is a double-stranded DNA virus with over 100 documented genotypes, approximately 40 of which are known to infect the oropharyngeal and anogenital tract. The genotypes are further classified as “low risk” for those that do not cause cervical cancer and “high risk” for those that can cause progression to cancer. There are at least 12 high risk or oncogenic types: HPV 16, 18, 31, 35, 39, 45, 51, 52, 54, 56, 58, 59, and limited evidence for HPV 66 and 68 to cause cancer. HPV contains eight genes within the double-stranded DNA that are characterized as either early (E) or late (L) genes. Early genes are produced early in the virus life cycle and are associated with DNA replication, regulatory functions and activation of the host cell cycle; late genes are involved with the production of viral capsid parts. Particular attention has focused on the so-called E6 and E7 genes since their expression is thought to be a signal of dysplastic cell transformation; the L1 region of the HPV gene is also of interest because it tends to exhibit the most variability from genotype to genotype. The goal of cervical cancer screening is to accurately detect high-grade precursor lesions of the cervix to allow timely treatment of cervical intraepithelial neoplasia (CIN). Persistent high-risk HPV infection is the causative agent of virtually all cervical cancers and its precursors,8 in vitro diagnostics (IVD) that can accurately detect high-risk HPV can be used both to identify women with existing precursor lesions and also to predict those who may be at risk for developing cervical precancer at a later date. IVDs that can detect HPV will therefore play an important role in cervical cancer prevention programmes. Access to screening and treatment of precancerous cervical lesions and management of cervical cancer remains a challenge for many women in low and middle-income countries, further highlighting inequities in women’s healthcare.
Healthcare-Provider Collected
To obtain a specimen for an HPV NAT IVD, a trained healthcare provider visualizes the cervix with a speculumv placed in the vagina and performs a scraping of cervical cells as shown in Figure 4. Various devices for specimen collection can be used and the manufacturer of the IVD will generally specify the appropriate collection device. The manufacturer’s instructions for use should always be followed. Cervical specimens collected by a healthcare provider are generally placed in a liquid transport medium that is specified by the manufacturer of the IVD.
Self-collected
One of the distinct advantages of HPV NAT IVDs over cytology in a cancer prevention programme is the option of using self-collected specimens rather than specimens collected in the clinic by trained healthcare providers. Unlike specimens for cytology testing that require collecting cells from the cervix under direct visualization, HPV specimens can be obtained from a self-collected vaginal swab, as shown in Figure 8.
HPV testing
HPV is a relatively small double stranded DNA virus that is present and accessible in infected exfoliated cell specimens, allowing detection by NAT IVDs.1 NAT technologies have led to the development of HPV IVDs for screening that focus on the qualitative detection of the high-risk genotypes.1,2 It is also known that HPV 16 and HPV 18 together are responsible for approximately 70% of all cervical cancers globally ; several HPV NAT IVDs have therefore been developed to specifically detect these most common oncogenic genotypes and in turn to identify those women at highest risk. The majority of HPV NAT IVDs are DNA-based where primers and probes are used to detect specific segments of HPV DNA. More recently, HPV IVDs have been developed to detect mRNA transcripts coding for the E6/E7.1,2 Among available commercial HPV NAT IVDs, results are generally reported out as “detected” or “not detected” for a pool of high-risk HPV genotypes; certain IVDs can also report out individual results in various combinations, for example: HPV 16 and 18; HPV 16, 18/45; HPV 16, 18, 45, 51, 52 with pooled results for 33/58, 56/59/66 and 35/39/68. Some HPV NAT IVDs that generate the individual genotype results require a reflex test run, while others are able to report out the individual results concurrently with the pooled result. When individual genotypes are reported out concurrently as an integrated step in the initial run, the time and resources needed for a second run are eliminated. For quality control, some HPV NAT IVDs are designed with an internal gene control to confirm specimen adequacy and acceptable assay performance; this is considered an important aspect of the test since it can potentially identify false negative results. False positive results can be minimized by the inclusion of a negative control that is capable of detecting contamination.
Performing HPV NAT IVDs
The commercially available HPV NAT IVDs span the spectrum of requiring significant manual pre-analytical, analytical and post-analytical steps to those where a fully automated system is utilized. The categories of IVDs are summarized in Table 2.
Clinical Performance
The sensitivity and specificity of an HPV IVD must be based on a clinically relevant endpoint to ensure that significant disease is not missed. For HPV NAT IVDs that are used as a screening assay in a cancer prevention programme, the sensitivity must be high enough to initially identify all women who are at risk of having or developing high grade precancerous lesions (CIN2 or greater), yet not too analytically sensitive so as to identify infection that is not likely to progress to disease. To optimize disease detection over transient HPV detection, clinical assays will generally select a cut-off for a “positive” (detected)/”negative” (not detected) result based on correlation to detection of CIN 2 or greater.