Human Papillomavirus
self-sampling could provide a very resource-efficient method able to reach thousands of women in the time only a fraction could be screened in a traditional clinic setting.20
Self-sampling is also preferred by women over
a traditional speculum exam. The surveys revealed that sometimes women would prefer to do the self-sampling close to a clinic where they ‘could get help’ if they have a problem, but consistently showed that, if a clinical setting was unavailable, women would prefer to do the sample at home rather than not at all.21
For many women, self-sampling would overcome the logistics of a clinic visit; clinics were either non-existent or required distant travel. Self-collection would also overcome objections from spouses or partners to the pelvic exam that exist in many cultures.22
We studied
self-sampling using swabs and brushes, while colleagues explored sampling with fluid washes and tampons.23,24
Most of the trials were carefully
crafted efforts trying to keep the process simple, acceptable, and inexpensive. Although self-collection need not be limited to underserved environments, this would clearly be more compelling. There were of course problems that needed to be solved.
The first problem encountered related to test performance or overall accuracy. Self-collected specimens tested for HR-HPV with hybrid capture 2 (HC 2) are not as sensitive or specific for CIN 2+ as practitioner-collected endocervical specimens.25
In our second Chinese study, SPOCCS II,26 in which
HC 2 was used to test for HR-HPV, the sensitivity for CIN 2+ of self-collected vaginal specimens (87.5 %) was lower than that of endocervical specimens (96.8 %, p<0.001); the specificity of the vaginal self-collected specimens for CIN 2+ (77.2 %) was also lower than that of endocervical specimens (79.7 %, p=0.001). Our third Chinese study (SPOCCS III)27
compared the specific
HPV types in self-collected vaginal and practitioner-collected endocervical specimens and again showed that, when compared with the endocervical practitioner-collected specimen, the vaginal self-collected specimen tested for HR-HPV by HC 2 had lower sensitivity (80.9 % versus 97.9 %, p=0.008) and lower specificity (88.6 % versus 90.2 %, p=0.001) for CIN 2+. Although these deficiencies of a self-collected specimen could be rationalized as a reasonable trade-off, since the methodology of self-sampling could reach so many more women, the investigations to improve self-collection technologies continued to move forward.
The previously mentioned SPOCCS III, we believe, explained the critical differences between a direct and a self-collected specimen.27
SPOCCS III
The discovery that a self-sample tested with a PCR- based assay (in this study, a linear array) provided sensitivity for self-collection equal to direct collection was particularly interesting. Unfortunately, at the time of this clinical trial, the PCR-based technologies were slow, expensive, laborious, and clearly not relevant to routine screening programs, which had as a major aim to take advantage of the benefits of self-collection.27
As a result of these studies, we developed a prototype for a self-sampling device, which had, in its final form after several small studies, a flocked nylon brush head that collected more cells, and a cardboard sleeve
114
suggested that a vaginal self-collected specimen would increase sensitivity for ≥CIN 3 if a larger (more cellular) specimen was collected selectively from the upper vagina or if a polymerase chain reaction (PCR)-based assay was used to test for HR-HPV. The decrease in specificity of the vaginal self-collected specimens was primarily due to HR-HPV present solely in the vagina, which is not associated with ≥CIN 3. Also affecting specificity to a lesser extent with HC 2 testing was the known cross-reaction with vaginal low-risk viral types.28
(tampon-like) to aid in selectively sampling the cervix and upper vagina. In the Shenzhen cervical cancer screening trial II (SHENCCAST II),29
we
tested the hypotheses from SPOCCS III in a 10,000 patient randomized clinical trial by comparing our self-collection device (the sixth generation self-sampler, realised in collaboration by Preventive Oncology International [POI] and the National Institutes of Health [NIH]) with the standard conical-shaped brush. We also compared the HR-HPV assays of Cervista® (which are virtually identical to HC 2)30
with the PCR-based
mass array matrix-assisted laser desorption/ionization time-of-flight mass spectrometry system (MALDI-TOF).31,32
We found that the POI/NIH
self-sampler was not effective in increasing the sensitivity of the vaginal self-collected specimens. When tested for HR-HPV with Cervista, the POI/NIH self-sampler had a similar sensitivity for CIN 3+ (71.6 %) as the conical-shaped brush (70.0 %, p=0.92). The sensitivity for ≥CIN 3 of vaginal self-collected specimens obtained with either sampling device and tested for HR-HPV by Cervista (70.9 %) remained lower than that of endocervical clinician-collected specimens tested by Cervista (95.0 %, p=0.0001). In contrast, the sensitivity for ≥CIN 3 of vaginal self-collected specimens obtained with either sampling device and tested for HR-HPV by the PCR-based MALDI-TOF (94.3 %) is identical to that of endocervical clinician-collected specimens tested for HR-HPV by MALDI-TOF (94.3 %, p=1.0) and similar to that of endocervical clinician-collected specimens tested by Cervista (95.0 %, p=0.5). As we expected, the specificity for ≥CIN 3 of vaginal self-collected specimens (87.5 % for MALDI-TOF and 86.1 % for Cervista) was lower was lower than that of endocervical clinician-collected specimens (89.4 %, p<0.0001 for MALDI-TOF and 90.3 %, p<0.0001 for Cervista).29
We speculate that the ineffectiveness
of the POI/NIH self-sampler in increasing the accuracy of the vaginal self-collected specimens for non-PCR-based testing was secondary to women being afraid to insert the sleeve to the top of the vagina or because the women did not fully understand that the sleeve needed to be retracted before obtaining the specimen. Tampon use is very uncommon in parts of the world with the highest rates of cervical cancer. This unfamiliarity, even with our efforts to instruct the women in the proper use of the self-sampler, surely was a contributing factor. We had had a similar problem in Mexico33
and, in addition to further
complexities in brush design, this would ultimately make the device too costly. We then decided that simplicity needed to be the key and that we would focus on the simplest and least expensive brush in the future.
Using HR-HPV testing of vaginal self-collected specimens as a primary screen for the prevention of cervical cancer has significant advantages compared with using endocervical clinician-collected specimens for HR-HPV or cervical cytology. The greatest advantage of this method is the ease with which a single individual can instruct the women and gather hundreds of self-collected samples per day.34
Also a PCR-based assay,
such as the linear array in our prior studies and MALDI-TOF in the current study, appears to have an analytical sensitivity that is optimally balanced for a self-collected sample.27
However, the critical difference between
MALDI-TOF and other PCR-based assays now tested with self-collection is that it has the capacity of very high throughput (4,500 samples/day) and a very low cost/case achievable with high volume processing.30
The result of these studies, in our opinion, is much bigger than we had anticipated. Now with the majority of the world’s medically underserved living in middle-income countries, it is no longer necessary to think small,
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