Present evidence on the value of HPV testing for cervical cancer screening: a model-based exploration of the (cost-)effectiveness

Abstract

Summary Human papillomavirus (HPV) is the main risk factor for invasive cervical cancer. High risk ratios are found in cross-sectional data on HPV prevalence. The question raised is whether this present evidence is sufficient for making firm recommendations on HPV screening. A validated cervical cancer screening model was extended by adding HPV infection as a possible precursor of cervical intraepithelial neoplasia (CIN). Two widely different model quantifications were constructed so that both were compatible with the observed HPV risk ratios. One model assumed a much longer duration of HPV infection before progressing to CIN and a higher sensitivity of the HPV test than the other. In one version of the model, the calculated mortality reduction from HPV screening was higher and the (cost-)effectiveness was much better than for Pap smear screening. In the other version, outcomes were the opposite, although the cost-effectiveness of the combined HPV + cytology test was close to that of Pap smear screening. Although small follow-up studies and studies with limited strength of design suggest that HPV testing may well improve cervical cancer screening, only large longitudinal screening studies on the association between HPV infection and the development of neoplasias can give outcomes that would enable a firm conclusion to be made on the (cost-)effectiveness of HPV screening. Prospective studies should address women aged 30-60 years.Keywords: cervical cancer; human papilloma virus; mass screening; Pap smear; cost-effectiveness Molecular and epidemiological studies have clearly demonstrated that HPV is the main risk factor for cervical cancer (IARC working group, 1995;Zur Hausen, 1994). These epidemiological studies are case-control studies that consistently show a very highrisk ratio for HPV in women with (precursors of) cervical cancer compared with controls with negative cytology (Morrison et al, 1991; Munoz et al, 1992; Elut-Neto et al, 1994;De SanJose et al, 1994). The association between CIN and high-risk HPV infection is stronger in high-grade than in low-grade abnormalities (van den Brule et al, 1991;Bergeron et al, 1992;Lorincz et al, 1992;Gaarenstroom, 1994; Kjear et al, 1996) and is well over 90% in invasive cancers (van den Brule et al, 1991;Bosch et al, 1995). A few small follow-up studies also corroborate the crucial role of HPV infections: progression is found almost only in women with (persistent) high-risk HPV genotypes both in normal (Rozendaal et al, 1996) and in dysplastic cases Remmink et al, 1995). In a small retrospective study on archived false-negative smears from women with subsequent invasive cervical cancer, the high-risk HPV types found in the cancers were detected in nearly 100% of the preceding smears (Munoz et al, 1992;Bauer et al, 1993;Cuzick et al, 1995;Rozendaal et al, 1996). This is much higher than can be explained by the life-time risk of developing cervical cancer in these countries. For example, in the Netherlands, the rate for high-risk HPV types in woman aged 30+ with norm...

Cumulative 5‐year diagnoses of CIN2, CIN3 or cervical cancer after concurrent high‐risk HPV and cytology testing in a primary screening setting

“…Moreover, our figures support the assumption that HPV related CIN even at younger age might be of minor predictive value for the development of cervical cancer. 3 In particular, in German-like settings with minimum age of 20 and annual screening, substantial modifications of the program will be necessary if HPV test is considered for primary screening. Preliminary cost-effectiveness models have shown that screening intervals for HPV and cytology negatives not only could but should be extended to avoid increasing diagnostic workup, surveillance and probably over-treatment of regressive lesions.…”

“…Whereas higher sensitivity and negative predictive value of HPV testing has been shown in several, mainly cross-sectional studies, the long-term impact on incidence and mortality has been evaluated in models only. 2,3 Thus, the current recommendations of various scientific societies and expert groups are controversial. The IARC working group on efficacy of cervical cancer screening concluded that there is sufficient evidence that HPV testing can reduce mortality from cervical cancer.…”

Cost‐effectiveness of primary cytology and HPV DNA cervical screening

“…9 Our results on preventive effect are also quite similar to a Dutch modeling study that found combined cytology and HPV DNA screening every 10 years from age 30 to 60 to reduce cervical cancer mortality with 91%, whereas cytology screening every 3 years from age 30 to 60 yielded a mortality reduction of 79%. 46 By contrast, studies using liquid based cytology and HPV DNA testing have reported costs from 121 USD to 184,000 USD per life year saved or per quality-adjusted life-year (QALY). [11][12][13][14][15][16][17][18][19][20][21][22] Possible reasons for discrepancies include the fact that we did not include screening of young women in our model, the setting with organized screening, the setting with midwives (who have lower salaries than doctors) for taking smears, population-based real-life input data and analysis using a probabilistic state transition model.…”

“…The number of diagnostic procedures, over-treatments and follow-up examinations is reduced by extending screening intervals, resulting in cost savings without changes in the clinical outcome, as found both by us and others. 46 Our study did not include hysterectomy rates in the model. Several studies have shown that about 10%-15% of the decrease in the cervical cancer incidence might be attributed to hysterectomies decreasing the population at risk.…”

“…Notable adverse effects are complications after conization like preterm delivery, anxiety caused by false positive test results and over treatment of nonprogressive CIN lesions. 46 The use of QALYs as outcome measures in cost-effectiveness modeling is recommended by the panel of cost-effectiveness in health and medicine 60 but no reliable studies are available allowing quantitation of quality of life aspects of screening and cervical cancer.…”