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Ongoing and Upcoming Studies

A Randomized, Placebo-Controlled Trial of HPV Vaccination to Reduce Cervical High-Grade Squamous Intraepithelial Lesions among HIV-Infected Women Participating in an HPV Test-and-Treat Program (COVENANT)

Summary

(Clinical lead, Dr.Lameck Chinula)

This randomized phase III trial studies how well human papillomavirus (HPV) vaccine therapy works in reducing high-grade cervical lesions in patients with human immunodeficiency virus (HIV) and HPV. Vaccines made from HPV peptides or antigens may help the body build an effective immune response to kill the HPV virus and prevent cervical lesions from developing or coming back after being removed.

At screening, potential participants will be tested for cervical human papillomavirus (HPV) infection (GeneXpert hrHPV assay and HPV DNA PCR) and undergo cervical colposcopy to confirm the absence of cervical cancer. If eligible, the participant will be randomized to receive either the 9-valent HPV vaccine or saline placebo.

Participants will return 4 and 26 weeks later for the second dose of vaccine or placebo. At week 4, participants will have cervical colposcopy and undergo cryotherapy or loop electrosurgical excisional procedure (LEEP) as appropriate. Participants undergoing cervical cryotherapy will have cervical biopsies before the treatment. Participants will be followed with HPV testing (Gene Xpert and HPV DNA PCR) at weeks 26, 52, 78, and 104, and will have cervical cytology and colposcopy with biopsies at weeks 26, 52, and 104.

A novel cervical cancer screen-and-treat demonstration project with HPV self-testing and thermocoagulation for HIV-infected women in Malawi

Summary

(PI, Dr.Lameck Chinula)

Invasive cervical cancer (ICC) kills 270,000 women/year, and 445,000 new cases are diagnosed annually. ICC is preventable with human papillomavirus (HPV) vaccination, cervical screening, and treatment of cervical dysplasia. However, 84% of new ICC cases occur in low-and-middle income countries (LMICs) such as Malawi, due to poor access to all three prevention strategies. This challenge is compounded in Sub-Saharan Africa (SSA), the epicenter of the HIV epidemic, because HIV-infected women are at increased risk for developing cervical dysplasia and have a >20-fold increased risk for ICC than HIV-uninfected women. In SSA, women comprise 59% of adults infected with HIV, and ICC is the most common cancer among women. The World Health Organization (WHO) recommends screening with high-risk (hr)-HPV testing/visual inspection with acetic acid (VIA) and treatment with cryotherapy as the preferred approach to prevent ICC in LMICs. Malawi has attempted to implement VIA and cryotherapy since 2004, but both screening and treatment rates remain abysmal. Furthermore, the HPV vaccine is not yet available in Malawi, and even when it does roll out in 2019, the vast majority of Malawian women will remain unvaccinated or age ineligible since, similar to other resource-limited SSA countries, only adolescent girls will be eligible for it. Even if widespread vaccination of adolescent girls is achieved, the consequent decline in ICC incidence is not anticipated for decades, and millions of African women will be missed. Therefore, an improved and scalable ICC prevention approach is urgently needed. We plan to evaluate a novel ICC screen-and-treat algorithm among HIV-infected women in Malawi with the following strategy: self-collected vaginal swabs for hr-HPV testing, followed by same-day VIA and cervical thermocoagulation for those who are VIA positive and eligible for ablation. This strategy has not yet been robustly evaluated, utilizes new technologies developed specifically for low-resource settings (rapid Xpert HPV testing, thermocoagulation), and can be completed in a single day. These attributes are likely to address the coverage and attrition problems that have limited current approaches.

Specifically, Aim 1 will assess same-day completion of this novel ICC screen-and-treat strategy among 625 HIV-infected women in Malawi, enrolled over 12 months from antiretroviral therapy clinics in the capital city of Lilongwe. Aim 2 will evaluate the performance of the proposed screen-and-treat strategy among HIV-infected women, by estimating the overtreatment rate for women who are hr-HPV positive/VIA positive and the undertreatment rate among HIV-infected women who are hr-HPV positive/VIA negative.Aim 3 will determine the 24-week efficacy of thermocoagulation among HIV- infected women with high-grade cervical dysplasia (CIN2/3). This study will provide essential data to inform national policy in Malawi and other countries where both HIV and ICC prevalence are high, and it will also facilitate applications for future cooperative clinical trials groups in cervical cancer and global oncology.


Completed

Safety and acceptability of a community-based screen-and-treat strategy of cervical cancer prevention in rural Lilongwe, Malawi

Summary

(PI, Dr.Lameck Chinula)

In 2004, Malawi adopted a cervical cancer control program with Visual Inspection with Acetic Acid (VIA) aimed at screening the largest possible proportion of women eligible for screening and ensuring appropriate management for all those who have an abnormal test result. VIA is inexpensive, utilizes locally-sourced supplies (vinegar acetic acid and cotton), and does not rely on laboratory services. It also allows for immediate results, and the client can be offered treatment at the same visit (i.e., the single visit approach or ‘screen and treat’ approach). Between 2005 and 2009, Malawi participated in a cervical cancer prevention demonstration project in collaboration with the World Health Organization (WHO). Providers were trained in VIA and cryotherapy to treat pre-cancerous lesions in line with WHO comprehensive cervical cancer control, and these services were rolled out in District Hospitals and other health facilities.

However, challenges in sourcing gas for cryotherapy and the high running costs have meant that women who require treatment for pre-cancerous lesions have not received treatment at all or have not received it in a timely manner. There is now increasing evidence demonstrating the effectiveness of thermo-coagulation (also called cold coagulation) for treatment of pre-cancerous lesions. Thermo-coagulation is well tolerated without anesthesia and safe for delivery in outpatient settings. However, there is limited data of the effectiveness of thermo-coagulation in SSA. Campbell et al demonstrated cure rates of 93.3% and 85% at 3–6 months and 12 months of follow-up, respectively, after treatment with thermo-coagulation. However, the cure rates were based on clinical outcomes with post-treatment VIA. Thus it is not known how many women treated with thermo-coagulation actually had pre-cancerous lesions (high grade cervical dysplasia) pre-treatment or post-treatment as neither pre-treatment nor post- treatment confirmatory cervical biopsies were performed. Considering that false abnormal VIA result could be caused by other conditions such as cervical squamous metaplasia, which is not precancerous, it is not known how many women were over-treated for lesions that resolve spontaneously with time or how many women with high grade dysplasia failed treatment.

VIA uptake has been poor, particularly in rural areas because of limited access to health services. There are numerous health system challenges such as failure to integrate cervical cancer screening services into existing reproductive health and HIV care services, which are directly and indirectly contributing to the low coverage of cervical cancer screening and treatment. Other known barriers to uptake of the screening services consist of long distances to health facilities, lack of transportation, and other costs. Furthermore, women who screen positive and are referred for treatment may not adhere to the referral recommendation. Screen-and-treat strategies reduce the number of visits required for women with abnormal VIA result that are treatable. Offering cervical cancer screening in a community-based campaign represents a potential solution to the problem of poor access.

There is paucity of data on the safety and acceptability of a community-based screen-and-treat strategy with VIA and thermo-coagulation for treatable pre-cancerous lesions in a community setting. We hypothesize that a community-based cervical cancer screening campaign will be an acceptable, safe, and effective complimentary strategy to the current health facility-based strategy, and that this approach will improve access to cervical cancer prevention services for women in rural Malawi. We therefore propose this research to evaluate the safety and acceptability of a community-based screen-and-treat strategy with VIA and thermo-coagulation through a campaign in rural Lilongwe, Malawi.