Nanotechnology-Based Screening for HPV: Rethinking Research Priorities and Outcomes

Abstract

The Gendered Innovations project was asked by the European Commission to analyze several of its Framework Programme 7 (FP7) projects. This case study examines the "Enhanced Sensitivity Nanotechnology-Based Multiplexed Bioassay Platform for Diagnostic Applications" (NANO-MUBIOP) project. We identify gendered innovations, methods of sex and gender analysis, and points of potential "value added."

The Challenge

Infection with Human Papillomavirus (HPV) "is estimated to cause […] 100% of cervical cancer cases," and contributes to the incidence of other cancers affecting both women and men, including anal cancer, oral and oropharyngeal cancers, and cancers of the genitals (WHO, 2008b). Worldwide, cervical cancer causes about 275,000 deaths per year - 80% in countries with limited medical resources (Sankaranarayanan et al., 2012). Existing HPV tests offer good sensitivity and specificity, but are rarely used in developing countries due to cost (Cuzick et al., 2008). A low-cost, high-performance test could improve healthcare in developing countries.

Method: Rethinking Research Priorities and Outcomes

In designing a new diagnostic technology, the NANO-MUBIOP project prioritized characteristics that would encourage adoption in diverse low-resource areas, such as Latin America and the Caribbean, sub-Saharan Africa, Melanesia, and South-Central and South-East Asia. These include technical characteristics - such as the ability to differentiate between specific types of HPV, which differ in epidemiology and oncogenicity - and practical, logistical characteristics - such as low overhead cost and simple implementation.

Gendered Innovations:

Developing a Low-Cost HPV Screening Test. NANO-MUBIOP seeks to develop a platform for inexpensive HPV testing.

Potential Value Added to Future Research through the Future Application of Gendered Innovations Methods

  1. Identifying potential users of the NANO-MUBIOP platform
  2. Understanding the causes of poor cervical cancer screening coverage

The Challenge
Background: The European Union Framework Programme 7 (FP7) Enhanced Sensitivity Nanotechnology-Based Multiplexed Bioassay Platform for Diagnostic Applications and Existing Strategies for Combating Cervical Cancer
Gendered Innovation 1: Developing a Low-Cost HPV Screening Test
Potential Value Added to Future Research through the Application of Gendered Innovations Methods
Potential Value Added 1: Identifying Potential Users
Method: Analyzing Factors Intersecting with Sex and Gender
Potential Value Added 2: Understand the Causes of Poor Cervical Cancer Screening
Method: Rethinking Research Priorities and Outcomes
Conclusions

The Challenge

Approximately 40 types of HPV are known to infect the genital tract (Trottier et al., 2009). Of these, 13 are classified as "high risk" for causing cervical cancer (Bhatla et al., 2010; Muñoz et al., 2003). HPV infection causes an estimated 100% of cervical cancer cases, and contributes to the incidence of other cancers affecting men specifically (penile cancer), women (vulvar cancer), and both women and men (anal cancer and several types of oral cancers) (WHO, 2008b).

The World Health Organization (WHO) has underscored the importance of screening, stating that "the introduction of HPV vaccine should not undermine or divert funding from effective screening programmes for cervical cancer" (WHO, 2009). Recent studies conducted in India and China indicate that affordable HPV DNA testing could significantly lower the incidence of advanced cervical cancer and mortality rates in low resource areas (Sankaranarayanan et al., 2009; Qiao et al., 2008). It should be noted that, like other screening programs, NANO-MUBIOP seeks to develop a platform for testing; it does not itself either prevent or treat HPV.

Background

The European Commission Framework Programme 7 (FP7) "Enhanced Sensitivity Nanotechnology-Based Multiplexed Bioassay Platform for Diagnostic Applications" (NANO-MUBIOP) and Existing Strategies for Combating Cervical Cancer

bio-probe array nanstructure on solid support

The NANO-MUBIOP project seeks to develop a bioassay platform, using nanoparticles, that is capable of detecting a target virus (for example, HPV) without DNA amplification. This platform, in an early stage of development, is planned as a heterogeneous bioassay method employing DNA probes specific for different DNA targets. Probes are arrayed on a solid substrate (slide). These slides would be exposed to DNA-containing analytes in the presence of carboxylated silica nanoparticles that would themselves be functionalized with generic probes complementary to DNA sequences in common to all DNA bio-targets (Fallani, 2010; Tóth et al., 2010; Tóth et al., 2012). The binding of these nanoparticles to DNA analytes would encourage and stabilize DNA binding to the probes on-substrate. Nanoparticles would then be detected optically—see schematic diagram on right showing the operation of NANO-MUBIOP.

Biological samples are to be directly analyzed by the NANO-MUBIOP platform, without previous amplification through polymerase chain reaction (PCR) or other methods. Functionalizing a substrate with multiple types of probes in specific regions could allow identification of multiple DNA targets—for example, variant DNA sequences in specific HPV types (Tóth et al., 2011; Liguri et al., 2010).

Comprehensive cervical cancer management includes screening, which might be performed with NANO-MUBIOP. Screening is vital because, with early detection, cervical cancer is highly treatable. In resource-rich countries, where cervical cancer is generally detected and treated in early stages, survival rates are much higher than in resource-poor countries, where detection generally occurs later and treatment is delayed or unavailable (Parkin et al., 2006). Many screening tests are in use. The chart at leftplaces NANO-MUBIOP in relation to cervical cancer prevention and screening--click to view.

Gendered Innovation 1: Developing a Low-Cost HPV Screening Test

NANO-MUBIOP researchers are working to develop an inexpensive HPV test. HPV tests exist, but high cost and complexity have limited adoption. NANO-MUBIOP seeks to provide:

  1. Low cost, on both a per-test basis and in terms of overhead for infrastructure needed to distribute and process tests (Trisolini et al., 2008a).
  2. 2. Minimal requirements for instrumentation and skilled operators, particularly in comparison to cytological and DNA methods, although a scanning or reading system will be needed (Trisolini et al., 2008a).
  3. 3. Rapid test results, especially when compared to other DNA testing methods (Trisolini et al., 2008a).
  4. 4. The ability to discriminate between specific HPV types (Trisolini et al., 2008a).
  5. 5. The ability to test samples from men as well as women (Fallani, 2010).

Potential Value Added to Future Research through the Application of Gendered Innovations Methods

Potential Value Added 1: Identifying Potential Users

Researchers might analyze factors intersecting with sex and gender to identify potential users of NANO-MUBIOP, and subsequently rethink research priorities and outcomes to design according to the needs of this target group—see Methods.

Method: Analyzing Factors Intersecting with Sex

HPV causes morbidity and mortality in both women and men worldwide, but the burden of HPV-related disease is unevenly distributed according to sex and geographic location:

  1. HPV-Related Diseases by Sex and Type: The majority of HPV-attributable cancers, an estimated 94%, occur in women because HPV causes more cases of cervical cancer than other cancer types (WHO, 2008b).
    Chart produced with data from Parkin et al., 2006.
  2. HPV-Related Diseases by Location: The majority of HPV-attributable cancers, an estimated 83%, occur in the developing world (Parkin et al., 2006). Deaths from cervical cancer are especially concentrated in resource-poor regions:

death from HPV by WHO member states 2004

Potential Value Added 2: Understand the Causes of Poor Cervical Cancer Screening

NANO-MUBIOP researchers seek to develop an HPV screening platform that can be used in developing countries (Trisolini et al., 2008a). Understanding the needs of this user group may require a further Method—see below.

Method: Rethinking Research Priorities and Outcomes

Cervical cancer screening could be enhanced through four specific innovations:

  1. 1. Reducing Costs to Increase Availability: Cervical cancer screening is highly cost-effective in both developed and developing countries—that is, the cost per life-year saved is very low in comparison to many other medical interventions (WHO, 2011; Goldhaber-Fiebert et al., 2008). However, cost remains an obstacle to adoption in developing countries; women in poor countries are much less likely to be screened than women in wealthier countries (Gakidou et al., 2008).

    Cervical cancer screening—whether performed by visual methods, cytological methods, or HPV testing—has costs associated with staff, "disposable supplies" (consumables), and "equipment and laboratory use" (instrumentation and infrastructure) (Goldie et al., 2005). NANO-MUBIOP researchers are seeking to reduce costs on all three fronts by creating a low-cost test that does not require skilled labor for implementation (as cytology tests do) and does not require access to a sophisticated molecular biology laboratory (as amplification-based HPV DNA tests often do) (Trisolini et al., 2008a).

  2. Automating Testing to Improve Quality Control: In countries where cervical cancer screening is available, healthcare can be compromised by low quality of screening services. In developing countries, about 45% of women have access to some form of cervical cancer screening, but only 19% have access to screening defined as effective (Gakidou et al., 2008). Quality control is particularly challenging for cytology-based tests (pap smears and liquid cytology).The labor-intensive nature of cytological screening and the extensive training needed to interpret test results can substantially compromise screening quality (Cuzick et al., 2008). NANO-MUBIOP researchers aim to overcome these obstacles by introducing an automated test (Trisolini et al., 2008c).
  3. Accelerating Testing to Allow Rapid Follow-Up: Conventional cervical cancer screening programs—particularly those based on cytology and HPV DNA testing—can have long follow-up times. Follow-up rates are often low, especially in developing countries with limited communication and transportation infrastructure (Bosch et al., 2008).
  4. Identifying HPV Subtypes to Enhance Specificity: Worldwide, there are modest differences in the burden of cervical cancer attributable to specific HPV types. For example, HPV types 16 and 18 cause 76% of cases in North America, but only 65% of cases in South and Central America, with intermediate values in other regions:


    The causes of observed differences in type-prevalence are not fully understood (Clifford et al., 2005). Some possibilities include:

    • Immunogenetics: People in different geographic areas may have different genetic polymorphisms which affect their susceptibility or resistance to specific HPV types (Hildesheim et al., 2002).
    • Prevalence of Other Infectious Diseases: Non-HPV infectious diseases may influence the risk of infection with specific HPV types. For example, HIV-related immune deficiency raises the risk of HPV-16 infection less than it raises the risk of infection with other HPV types (Strickler et al., 2003). This might explain why HPV types other than HPV-16 are a more important cause of cervical cancer in Africa (where HIV is relatively prevalent) than in Europe (where HIV is less prevalent) (Clifford et al., 2005).
    • Prevalence of Non-Infectious Diseases and Conditions: Malnutrition may contribute to higher incidence of non-HPV-16 types in resource-poor areas (Clifford et al., 2005).

Regardless of cause, the heterogeneity of HPV type prevalence underscores the potential usefulness of a test able to detect multiple types.

In addition to geographic differences in prevalence, different types of HPV vary in their propensity to cause specific types of cervical cancer (Dahlström et al., 2010). For example, "HPV-18 is more often associated with difficult to detect or visualize lesions in the endocervical canal" than certain other types (Cuzick et al., 2008). For these reasons, detection of specific HPV types has potential therapeutic value, and NANO-MUBIOP researchers have made multiplexing a key development priority (Trisolini et at., 2008a).

Conclusion

The NANO-MUBIOP project has identified key needs for HPV testing in both the developed and developing worlds. Although still in development, NANO-MUBIOP seeks to produce a test which can detect HPV reliably and rapidly in both women and men, and are concentrating on using automation to minimize the high personnel costs typical of existing HPV tests. NANO-MUBIOP researchers have produced laboratory prototypes, but much work remains to be done before the platform can be clinically validated (Fallani, 2010).

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The Gendered Innovations project was asked by the European Commission to analyze several of its Framework Programme 7 (FP7) projects. "Enhanced Sensitivity Nanotechnology-Based Multiplexed Bioassay Platform for Diagnostic Applications" (NANO-MUBIOP) seeks to develop a low-cost HPV screening test. We identify gendered innovations, methods of sex and gender analysis, and points of potential "value added" through the future application of gendered innovations methods.

Gendered Innovation:

Approximately 40 types of HPV are known to infect the genital tract. HPV infection causes an estimated 100% of cervical cancer cases, and contributes to the incidence of other cancers affecting men specifically (penile cancer), women (vulvar cancer), and both women and men (anal cancer and several types of oral cancers).

NANO-MUBIOP is working to develop an inexpensive HPV test. HPV tests exist, but high cost and complexity have limited adoption.

Potential Value Added to Future Research through the Future Application of Gendered Innovations Methods:

NANO-MUBIOP seeks to develop an HPV screening platform that can be used in developing countries. Understanding the needs of this user group may require Analyze Factors Intersecting with Sex and Gender and Rethinking Research Priorities and Outcomes. An estimated 83% of HPV-attributable cancers occur in the developing world. In designing new diagnostic technology, the NANO-MUBIOP project is prioritizing characteristics that would encourage adoption in diverse low-resource areas, such as Latin America and the Caribbean, sub-Saharan Africa, Melanesia, and South-Central and South-East Asia.