Development and clinical validation of a multi-type HPV E6/E7 oncoprotein test for cervical cancer screening and triage in low- and middle-income countries

Cervical cancer remains a leading cause of cancer incidence and mortality in most low and middle income countries (LMIC). Despite cytology based screening programs have reduce cervical cancer mortality up to 80% in developed nations, these programs have frequently failed success in developing countries mainly due to the requirement of multiple visits to identify women at risk who require treatment. The low sensitivity of cervical cytology (around 50%) induces the frequent repetition of the test through lifetime screening; in addition, the complementary diagnosis with colposcopy-biopsy requires women to attend multiple visits in the short time to undergo proper treatment. Recently, highly sensitive and reproducible laboratory techniques to detect carcinogenic HPV have been developed and approved by FDA as primary cervical cancer screening tests. Randomized clinical trials have demonstrated that HPV testing is more sensitive than cytology to detect cervical cancer precursors (around 90% vs 50%) and it has also been shown that HPV testing detects more disease at an earlier stage and induces a greater reduction in cervical cancer mortality. These technologies are changing screening practices in low and middle income countries such as Mexico, Argentina, Colombia, and El Salvador. Despite its advantages, HPV tests have a low positive predictive value; thus, they require additional diagnostic procedures (triage) to avoid overburden of colposcopy clinics or overtreatment if no confirmatory diagnosis is performed (see-and-treat programs). Currently, the triage for positive women is done with cytology, which again, due to the low sensitivity produces a high recall rate challenging screening programs in low resource settings. At the moment none of the triage tests under investigation is suitable for screening programs in LMIC due to the induction of high recall rates or high logistic or infrastructure requirements for its implementation. The development of a highly accurate test in a friendly/manual format producing results on individual basis will help improve outcomes of screening programs in low resource settings. We will use the platform of a cervical cancer research network already in place in Latin American countries (LAC) to: (Aim 1) developed and improved HPV test based on E6/E7 oncoprotein activity for the 8 most common HPV types associated with cervical cancer; (Aim 2) assess the potential clinical performance of the 8-HPV type E6/E7-based OncoProtein Cervical Test by challenging it against the whole spectrum of disease's histological diagnosis in 800 samples; (Aim 3) asses the sensitivity and specificity of the test for the detection of cancer precursors among HPV positive women (triage) in 4,500 women from the ESTAMPA study; (Aim 4) assess the potential of the test as standalone test for cervical cancer screening by using a sample of additional 1,000 HPV negative women; (Aim 5) to compare the results (positive/negative) of the 8-HPV type E6/E7-based OncoProtein Cervical Test with HPV persistence and development of cervical lesions after 18 months of women follow-up; (Aim 6) identify differences in the performance of test in different settings by processing 4,500 samples in three different labs in LAC; (Aim 7) identify operational requirements for scaling up cervical cancer screening programs based on the 8-HPV type E6/E7-based OncoProtein Cervical Test by performing 1,500 samples in real time in five different LAC; (Aim 8) describe differences in sensitivity and specificity between the origina OncoE6TM Cervical Test that included oncoproteins for HPV 16 and 18 and the new 8-HPV type E6/E7-based OncoProtein Cervical Test.