Browsing by Author "Brown, Darron"

Now showing 1 - 9 of 9
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    Clarification on the impact of cervarix vaccination on human papillomavirus infection and cervical cancer in the United Kingdom
    (Taylor & Francis, 2016-07-02) Brown, Darron; Kulkarni, Amit Sharad; Pillsbury, Matt; Luxembourg, Alain; Saah, Alfred; Department of Medicine, IU School of Medicine
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    A community-based approach to cervical cancer prevention in western Kenya: An AMPATH feasibility project
    (Sage, 2022-05-23) Orang’o, Omenge; Tonui, Philip; Muthoka, Kapten; Kiptoo, Stephen; Maina, Titus; Agosa, Mercy; Ermel, Aaron; Tong, Yan; Brown, Darron; Medicine, School of Medicine
    Objectives: Centralized programs have been ineffective in reducing the burden of cervical cancer among Kenyan women. A community-based pilot study was initiated to screen Kenyan women for cervical cancer and to vaccinate their children against human papillomavirus (HPV). Methods: Women were educated about cervical cancer prevention at community meetings. Women then provided self-collected vaginal swabs for oncogenic HPV testing using the Roche Cobas Assay. All women were then referred to the local clinic for Visual Inspection with Acetic Acid (VIA). Women were offered the quadrivalent HPV vaccine for their children if and when it became available for the study. Results: Women in western Kenya were invited to participate in community meetings. A total of 200 women were enrolled: 151 (75.5%) were HIV-uninfected and 49 (24.5%) were HIV-infected; the median age for all women was 42 years. High-risk (HR)-HPV types were detected in 49 of swabs from all 200 participants (24.5%) including 20.5% of HIV-uninfected women and 36.7% of HIV-infected women (P = .022). VIA was performed on 198 women: 192 had normal examinations and six had abnormal examinations. Five cervical biopsies revealed two cases of CIN 2 and one CIN 3. Although all mothers were willing to have their children (N = 432) vaccinated, the HPV vaccine could not be delivered to Kenya during the study period. Conclusions: Kenyan women were willing to attend community meetings to learn about prevention of cervical cancer, to provide self-collected vaginal swabs for HPV testing, to travel to the Webuye Clinic for VIA following the collection of swabs, and to have their children vaccinated against HPV. HR-HPV was prevalent, especially in HIV-infected women. As a result of this pilot study, this community-based strategy to prevent cervical cancer will be continued in western Kenya.
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    Detection of types of HPV among HIV-infected and HIV-uninfected Kenyan women undergoing cryotherapy or loop electrosurgical excision procedure
    (Wiley, 2020-11) Orang’o, Elkanah O.; Emont, Jordan P.; Ermel, Aaron C.; Liu, Tao; Omodi, Victor; Tong, Yan; Itsura, Peter M.; Tonui, Philip K.; Maina, Titus; Ong’echa, John M.; Muthoka, Kapten; Kiptoo, Stephen; Moormann, Ann; Hogan, Joseph; Loehrer, Patrick J.; Brown, Darron; Cu-Uvin, Susan; Medicine, School of Medicine
    Objective: To assess the baseline types of HPV infection among HIV-positive and HIV-negative women in western Kenya undergoing cryotherapy or loop electrosurgical excision procedure (LEEP) for cervical intraepithelial neoplasia. Methods: A prospective observational study was conducted of baseline HPV characteristics of women undergoing visual inspection with acetic acid (VIA) and cryotherapy or LEEP. After a positive VIA in HIV-positive and HIV-negative women, data on demographics, CD4 count, and use of antiretroviral therapy and a cervical swab were collected. HPV typing was performed using the Roche Linear Array. Results: Of 175 participants, 86 (49.1%) were HIV-positive and had a higher prevalence of low-risk HPV types (odds ratio [OR] 5.28, P=0.005) compared with HIV-negative women. The most common high-risk (HR)-HPV types in HIV-positive women were HPV 16 (13.9%) and HPV 18 (11.1%). HIV-positive women requiring LEEP were more likely to have HR-HPV types (OR 6.67, P=0.012) and to be infected with multiple HR-HPV types (OR 7.79, P=0.024) compared to those undergoing cryotherapy. Conclusion: HIV-positive women requiring LEEP versus cryotherapy had a higher prevalence of any HR-HPV type and multiple HR-HPV types. There were no such differences in HPV types identified among HIV-negative women.
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    E7 PROTEINS OF HIGH-RISK (TYPE 16) AND LOW-RISK (TYPE 6) HUMAN PAPILLOMAVIRUSES REGULATE p130 DIFFERENTLY
    (2010-10-15) Barrow, Lisa C.; Roman, Ann; Brown, Darron; He, Johnny J.; Nakshatri, Harikrishna
    Human papillomaviruses (HPVs) are one of the most common causes of sexually transmitted disease in the world. HPVs are divided into high-risk (HR) or low-risk (LR) types based on their oncogenic potential. HPVs 16 and 18 are considered HR types and can cause cervical cancer. HPVs 6 and 11 are classified as LR and are associated with condyloma acuminata (genital warts). Viral proteins of both HR and LR HPVs must be able to facilitate a replication competent environment. The E7 proteins of LR and HR HPVs are responsible for maintenance of S-phase activity in infected cells. HR E7 proteins target all pRb family members (pRb, p107 and p130) for degradation. LR E7 does not target pRb or p107 for degradation, but does target p130 for degradation. Immunohistochemistry experiments on HPV 6 infected patient biopsies of condyloma acuminata showed that detection of p130 was decreased in the presence of the whole HPV 6 genome. Further, the effect of HR HPV 16 E7 and LR HPV 6 E7 on p130 intracellular localization and half-life was examined. Experiments were performed using human foreskin keratinocytes transduced with HPV 6 E7, HPV 16 E7 or parental vector. Nuclear/cytoplasmic fractionation and immunofluorescence showed that, in contrast to control and HPV 6 E7-expressing cells, a greater amount of p130 was present in the cytoplasm in the viii presence of HPV 16 E7. The half-life of p130, relative to control cells, was decreased in the cytoplasm in the presence of HPV 6 E7 or HPV 16 E7, but only decreased by HPV 6 E7 in the nucleus. Inhibition of proteasomal degradation extended the half-life of p130, regardless of intracellular localization. Experiments were also conducted to detect E7-binding partners. Cyclin C and cullin 5 were identified as proteins capable of binding to both HPV 6 E7 and HPV 16 E7. Preliminary experiments showed that decreasing protein levels of p600, a binding partner of both HPV 6 E7 and HPV 16 E7, by RNA interference might affect p130 stability. Elucidating the mechanisms of p130 degradation may identify potential targets for preventing degradation of p130 and allowing restoration of cell cycle control.
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    Evidence for cross-protection but not type-replacement over the 11 years after human papillomavirus vaccine introduction
    (Landes Bioscience, 2019) Covert, Courtney; Ding, Lili; Brown, Darron; Franco, Eduardo L.; Bernstein, David I.; Kahn, Jessica A.; Medicine, School of Medicine
    Examination of cross-protection and type replacement after human papillomavirus (HPV) vaccine introduction is essential to guide vaccination recommendations and policies. The aims of this study were to examine trends in non-vaccine-type HPV: 1) genetically related to vaccine types (to assess for cross-protection) and 2) genetically unrelated to vaccine types (to assess for type replacement), among young women 13-26 years of age during the 11 years after HPV vaccine introduction. Participants were recruited from a hospital-based teen health center and a community health department for four cross-sectional surveillance studies between 2006 and 2017. Participants completed a survey that assessed sociodemographic characteristics and behaviors, and cervicovaginal swabs were collected and tested for 36 HPV genotypes. We determined changes in proportions of non-vaccine-type HPV prevalence and conducted logistic regression to determine the odds of infection across the surveillance studies, propensity-score adjusted to control for selection bias. Analyses were stratified by vaccination status. Among vaccinated women who received only the 4-valent vaccine (n = 1,540), the adjusted prevalence of HPV types genetically related to HPV16 decreased significantly by 45.8% (adjusted odds ratio [AOR] = 0.48, 95% confidence interval [CI] = 0.31-0.74) from 2006-2017, demonstrating evidence of cross-protection. The adjusted prevalence of HPV types genetically related to HPV18 did not change significantly (14.2% decrease, AOR = 0.83, 95% CI = 0.56-1.21). The adjusted prevalence of HPV types genetically unrelated to vaccine types did not change significantly (4.2% increase, AOR = 1.09, CI = 0.80-1.48), demonstrating no evidence of type replacement. Further studies are needed to monitor for cross-protection and possible type replacement after introduction of the 9-valent HPV vaccine.
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    Human papillomavirus detection in cervical neoplasia attributed to 12 high-risk human papillomavirus genotypes by region
    (Elsevier, 2016-12) Castellsagué, Xavier; Ault, Kevin A.; Bosch, F. Xavier; Brown, Darron; Cuzick, Jack; Ferris, Daron G.; Jours, Elmar A.; Garland, Suzanne M.; Giuliano, Anna R.; Hernandez-Avila, Mauricio; Huh, Warner; Iversen, Ole-Erik; Kjaer, Susanne K.; Luna, Joaquin; Monsonego, Joseph; Muñoz, Nubia; Myers, Evan; Paavonen, Jorma; Pitisuttihum, Punnee; Steben, Marc; Wheeler, Cosette M.; Perez, Gonzalo; Saah, Alfred; Luxembourg, Alain; Sings, Heather L.; Velicer, Christine; Department of Medicine, IU School of Medicine
    Background We estimated the proportion of cervical intraepithelial neoplasia (CIN) cases attributed to 14 HPV types, including quadrivalent (qHPV) (6/11/16/18) and 9-valent (9vHPV) (6/11/16/18/31/33/45/52/58) vaccine types, by region Methods Women ages 15–26 and 24–45 years from 5 regions were enrolled in qHPV vaccine clinical trials. Among 10,706 women (placebo arms), 1539 CIN1, 945 CIN2/3, and 24 adenocarcinoma in situ (AIS) cases were diagnosed by pathology panel consensus. Results Predominant HPV types were 16/51/52/56 (anogenital infection), 16/39/51/52/56 (CIN1), and 16/31/52/58 (CIN2/3). In regions with largest sample sizes, minimal regional variation was observed in 9vHPV type prevalence in CIN1 (~50%) and CIN2/3 (81–85%). Types 31/33/45/52/58 accounted for 25–30% of CIN1 in Latin America and Europe, but 14–18% in North America and Asia. Types 31/33/45/52/58 accounted for 33–38% of CIN2/3 in Latin America (younger women), Europe, and Asia, but 17–18% of CIN2/3 in Latin America (older women) and North America. Non-vaccine HPV types 35/39/51/56/59 had similar or higher prevalence than qHPV types in CIN1 and were attributed to 2–11% of CIN2/3. Conclusions The 9vHPV vaccine could potentially prevent the majority of CIN1-3, irrespective of geographic region. Notwithstanding, non-vaccine types 35/39/51/56/59 may still be responsible for some CIN1, and to a lesser extent CIN2/3.
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    Human papillomavirus type distribution in cervical cancer in Indiana and Botswana
    (2014) Qadadri, Brahim; Goebl, Mark G.; Harrington, Maureen A.; Brown, Darron
    In this study we compared the distribution of HPV types in cervical cancer specimens from women living in either Indiana or Botswana. Paraffin-embedded blocks of formalin-fixed cervical cancer specimens were identified from women living in Indiana (n=51) or Botswana (n=171)
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    Real time PCR and fluorescent in situ hybridization in the detection of the physical tsate of human papillomavirus 16 and 18 in paraffin embedded cervical tissue
    (2015-07) Davis, Aisha; Brown, Darron; Ermel, Aaron C.; Johnson, Raymond
    Human papillomaviruses (HPV) are the etiologic agents of most cervical dysplasia and all cervical carcinoma. Integration of high risk HPV into the human genome is thought to be a critical event in the progression from cervical dysplasia to invasive cervical carcinoma. The ability to use molecular assays in the detection and evaluation of HPV integration is essential in informing clinical models for early intervention and therapies. We therefore sought to determine the feasibility of real time-PCR (RT-PCR) as a molecular tool in detecting the physical state, episomal versus integration of HPV 16 and 18 DNA in cervical cancers. Tyramide amplified fluorescent DNA in situ hybridization (FISH) was used to look for evidence of HPV 16/18 integration using formalin-fixed, paraffin-embedded sections of cervical carcinomas. RT-PCR used the ratio of the E2 and E6 genes as a surrogate for determining the physical state of HPV 16 and 18 in 35 infected tissues. Results of RT-PCR showed that 16 cervical specimens (45.7%) contained episomal HPV, 17 cervical samples (48.6%) harbored the integrated form of HPV DNA, and 2 samples (5.7 %) contained both integrated and episomal forms of HPV. Results of the two assays were compared in 25 cervical carcinomas. For 13 of the 25 cervical samples there was an agreement in determining the physical state of HPV. RT-PCR, using the E2/E6 ratio as an assay for HPV integration appears to be promising and may prove to be an essential clinical method in the future.
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    Real-World Cervical Cancer Screening Uptake and Predictors of Visual Inspection With Acetic Acid Positivity Among Women Living With HIV in Care Programs in Western Kenya
    (American Society of Clinical Oncology, 2024) Mungo, Chemtai; Orang’o, Omenge; Ofner, Susan; Musick, Beverly; Yiannoutsos, Constantin; Cohen, Craig R.; Brown, Darron; Wools-Kaloustian, Kara; Semeere, Aggrey; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
    Purpose: To achieve the WHO cervical cancer elimination targets, countries globally must achieve 70% cervical cancer screening (CCS) coverage. We evaluated CCS uptake and predictors of screening positive at two public HIV care programs in western Kenya. Methods: From October 2007 to February 2019, data from the Family AIDS Care and Education Services (FACES) and Academic Model Providing Access to Healthcare (AMPATH) programs in western Kenya were analyzed. The study population included women age 18-65 years enrolled in HIV care. Screening uptake was calculated annually and overall, determining the proportion of eligible women screened. Multivariate logistic regression assessed predictors of positive screening outcomes. Results: There were 57,298 women living with HIV (WLWHIV) eligible for CCS across both programs during the study period. The mean age was 31.4 years (IQR, 25.9-37.8), and 39% were on antiretroviral therapy (ART) at the first CCS-eligible visit. Of all eligible women, 29.4% (95% CI, 29.1 to 29.8) underwent CCS during the study period, 27.0% (95% CI, 26.5 to 27.4) in the AMPATH program, and 35.6% (95% CI, 34.9 to 36.4) in the FACES program. Annual screening uptake varied greatly in both programs, with coverage as low as 1% of eligible WLWHIV during specific years. Age at first screening, CD4 count within 90 days of screening, current use of ART, and program (AMPATH v FACES) were each statistically significant predictors of positive screening. Conclusion: CCS uptake at two large HIV care programs in Kenya fell short of the WHO's 70% screening target. Screening rates varied significantly on the basis of the availability of funding specific to CCS, reflecting the limitations of vertical funding programs.