Assessing the diagnostic value of Xpert HPV – Authors' reply
Authors: Louise Kuhn, Rakiya Saidu, Lynette Denny
Journal: The Lancet Global Health (2020)

We thank Siamak Sabour for drawing attention to the importance of the public health relevance of diagnostic accuracy for cervical cancer screening tests. Indeed Dr Sabor is correct in pointing to some reluctance from practitioners to implement human papillomavirus (HPV)-based screen-and-treat, despite the high sensitivity of HPV testing, because of its relatively low specificity, especially in women living with HIV. In our Article,1Kuhn L Saidu R Boa R et al.Clinical evaluation of modifications to a human papillomavirus assay to optimise its utility for cervical cancer screening in low-resource settings: a diagnostic accuracy study.Lancet Glob Health. 2020; 8: e296-e304Summary Full Text Full Text PDF PubMed Scopus (16) Google Scholar Xpert HPV, similar to other HPV tests, has excellent sensitivity, but specificity is suboptimal, particularly in women living with HIV. The primary aim of our study was to show that using existing output from the Xpert HPV assay, the balance between sensitivity and specificity can be improved. With these adjustments, this assay is ideal for HPV-based screen-and-treat, even in populations with a high population of women living with HIV. Xpert HPV provides aggregate HPV typing of the 14 high-risk HPV types in five fluorescent channels: HPV 16 (channel 1), HPV 18 and 45 (channel 2), HPV 31, 33, 35, 52, and 58 (channel 3), HPV 51 and 59 (channel 4), and HPV 39, 56, 66, and 68 (channel 5). The assay is a real-time PCR and cycle threshold values are reported for each channel, the resulting output provides the classification as positive or negative based on the established cycle threshold cut-offs. Our study showed that selecting more stringent cycle threshold cut-offs on the three channels detecting HPV types 16, 18, 45, 31, 33, 35, 52, 58 (ie, allowing the assay to be slightly less sensitive) leads to levels of specificity acceptable for the screen-and-treat approach, even for women living with HIV. In our study, if we set the cut-offs of the assay so that the sensitivity is 80%, we attained a specificity of 94·1% in women without HIV and a specificity of 83·2% in women living with HIV. Sensitivity and specificity are intrinsic properties of a screening test, whereas positive predictive value (PPV), negative predictive value (NPV), and percentage of the population who screen positive are driven by the prevalence of disease in a population. In our South African study population, setting the cut-offs so that sensitivity is set at 80%, leads to a PPV of 43·1%, NPV of 98·8%, and a screen-positive rate of 9·8% in women without HIV. For women living with HIV, it leads to a PPV of 49·4%, NPV of 95·3%, and screen-positive rate of 27·5%. These are highly attractive parameters for an effective HPV-based screen-and-treat programme and are a considerable improvement over HPV testing without this modification. Although our study evaluated Xpert HPV, other HPV tests with capacity to disentangle separate HPV types and quantify viral load could be adapted in a similar way. Moreover, we used 80% sensitivity, but programmes could select higher or lower levels of sensitivity depending on resources available and community preferences and could adjust the cut-offs accordingly. We declare no competing interests. Clinical evaluation of modifications to a human papillomavirus assay to optimise its utility for cervical cancer screening in low-resource settings: a diagnostic accuracy studyMore stringent cycle threshold cutoffs on selected channels in Xpert HPV improve specificity with only modest losses in sensitivity, making this assay an optimal choice for HPV-based screen and treat in settings with a high prevalence of HIV. These modifications can be made from standard output with no need for new engineering. Decision making about performance characteristics of HPV testing can be shifted to programme implementers and cutoffs selected according to resource availability and community preferences. Full-Text PDF Open AccessAssessing the diagnostic value of Xpert HPVHuman papillomavirus (HPV)-based screen-and-treat is the recommended approach for cervical cancer screening in low-resource settings, but the relatively low specificity of HPV testing, particularly in women living with HIV, leads to overtreatment. In their diagnostic accuracy study, Louise Kuhn and colleagues (February, 2020)1 aimed to evaluate whether HPV type restriction and more stringent cycle threshold cutoffs on Xpert HPV optimise performance characteristics of this assay for screen-and-treat. Full-Text PDF Open Access