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Large-scale epidemiologic studies have been invaluable for elaboration of the causal relationship between persistent detection of genital human papillomavirus (HPV) infection and the development of invasive cervical cancer. However, these studies provide limited data to adequately inform models of the individual-level natural history of HPV infection over the course of a lifetime, and particularly ignore the biological distinction between HPV-negative tests and lack of infection (i.e., the possibility of latent, undetectable HPV infection). Using data from more recent epidemiological studies, this review proposes an alternative model of the natural history of genital HPV across the life span. We argue that a more complete elucidation of the age-specific probabilities of the alternative transitions is highly relevant with the expanded use of HPV testing in cervical cancer screening. With routine HPV testing in cervical cancer screening, women commonly transition in and out of HPV detectability, raising concerns for the patient and the provider regarding the source of the positive test result, its prognosis, and effective strategies to prevent future recurrence. Alternative study designs and analytic frameworks are proposed to better understand the frequency and determinants of these transition pathways.

Human papillomavirus 16 (HPV16) species group (alpha-9) of the Alphapapillomavirus genus contains HPV16, HPV31, HPV33, HPV35, HPV52, HPV58 and HPV67. These HPVs account for 75% of invasive cervical cancers worldwide. Viral variants of these HPVs differ in evolutionary history and pathogenicity. Moreover, a comprehensive nomenclature system for HPV variants is lacking, limiting comparisons between studies. DNA from cervical samples previously characterized for HPV type were obtained from multiple geographic regions to screen for novel variants. The complete 8 kb genomes of 120 variants representing the major and minor lineages of the HPV16-related alpha-9 HPV types were sequenced to capture maximum viral heterogeneity. Viral evolution was characterized by constructing phylogenic trees based on complete genomes using multiple algorithms. Maximal and viral region specific divergence was calculated by global and pairwise alignments. Variant lineages were classified and named using an alphanumeric system; the prototype genome was assigned to the A lineage for all types. The range of genome-genome sequence heterogeneity varied from 0.6% for HPV35 to 2.2% for HPV52 and included 1.4% for HPV31, 1.1% for HPV33, 1.7% for HPV58 and 1.1% for HPV67. Nucleotide differences of approximately 1.0% - 10.0% and 0.5%-1.0% of the complete genomes were used to define variant lineages and sublineages, respectively. Each gene/region differs in sequence diversity, from most variable to least variable: noncoding region 1 (NCR1) /noncoding region 2 (NCR2) >upstream regulatory region (URR)> E6/E7 > E2/L2 > E1/L1. These data define maximum viral genomic heterogeneity of HPV16-related alpha-9 HPV variants. The proposed nomenclature system facilitates the comparison of variants across epidemiological studies. Sequence diversity and phylogenies of this clinically important group of HPVs provides the basis for further studies of discrete viral evolution, epidemiology, pathogenesis and preventative/therapeutic interventions.

The discovery that certain high-risk strains of human papillomavirus (HR-HPV) cause nearly 100% of invasive cervical cancer has spurred a revolution in cervical cancer prevention by promoting the development of viral vaccines. Although the efficacy of these vaccines has already been demonstrated, a complete understanding of viral latency and natural immunity is lacking, and solving these mysteries could help guide policies of cervical cancer screening and vaccine use. Here, we examine the epidemiological and biological understanding of the natural history of HPV infection, with an eye toward using these studies to guide the implementation of cervical cancer prevention strategies.

Background Cervical cancer is preventable with vaccination and early detection and treatment programs. However, for these programs to work as intended, stigma related to HPV and cervical cancer must be understood and addressed. We explored pre-existing stigma associated with HPV and cervical cancer in the public healthcare system and community of a low-resource setting prior to implementation of an HPV screen-and-treat program. Methods This study conducted thematic analysis of data collected during implementation of a novel HPV screen-and-treat system for cervical cancer early detection and treatment in Iquitos, Peru. We included 35 semi-structured interviews (19 health professionals, 16 women with cervical precancer or cancer), eight focus groups (70 community women), one workshop (14 health professionals), 210 counseling observations (with 20 nurse-midwives), and a document review. We used the Socio-Ecological Model to organize the analysis. Results We identified three main themes: 1. the implication that women are to blame for their HPV infection through characterizations of being easy or promiscuous, 2. the implication that men are to blame for women’s HPV infections through being considered careless or unfaithful, 3. HPV is shameful, embarrassing, and something that should be hidden from others. Consequently, in some cases, women refrained from getting screened for HPV. These themes were seen at the individual level among women, relationship level among women, men, and family members, community level among healthcare staff, and societal level within components of cervical cancer guidelines and male chauvinism. Conclusions Cervical cancer early detection and treatment programs in limited resource settings must address stigma entrenched throughout the entire healthcare system and community in order to sustainably and successfully implement and scale-up new programs. Interventions to tackle this stigma can incorporate messages about HPV infections and latency to lessen the focus on the influence of sexual behavior on HPV acquisition, and instead, promote screening and treatment as paramount preventative measures.

Male circumcision has been shown to reduce the acquisition of the human immunodeficiency virus (HIV) in circumcised men. In two studies in Uganda involving 3393 adolescent boys and men who were seronegative for HIV and for herpes simplex virus type 2 (HSV-2), circumcision reduced the acquisition of HSV-2 and the prevalence of high-risk human papillomavirus (HPV) infection but not the acquisition of syphilis. In two studies in Uganda, circumcision reduced the acquisition of herpes simplex virus type 2 (HSV-2) and the prevalence of high-risk human papillomavirus (HPV) infection but not the acquisition of syphilis. Herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) infections and syphilis are common sexually transmitted infections. HSV-2 infection and syphilis are two of the main causes of genital ulceration 1 – 3 and have been associated with an increased risk of human immunodeficiency virus (HIV) infection in observational studies. 1 , 2 , 4 The prevalence of HPV is significantly increased in developing nations. 5 HPV infection can cause genital warts, and high-risk HPV genotypes are associated with penile and anal cancer, as well as with cervical cancer in female partners. 5 , 6 Three randomized trials and multiple observational studies showed that male circumcision significantly . . .

While many studies have compared the efficacy of Pap cytology, visual inspection with acetic acid (VIA) and human papillomavirus (HPV) DNA assays for the detection cervical intraepithelial neoplasia and cancer, few have evaluated the program effectiveness. A population-based sample of 5603 women from Medchal Mandal in Andhra Pradesh, India were invited to participate in a study comparing Pap cytology, VIA, and HPV DNA screening for the detection of CIN3+. Participation in primary screening and all subsequent follow-up visits was rigorously tracked. A 20% random sample of all women screened, in addition to all women with a positive screening test result underwent colposcopy with directed biopsy for final diagnosis. Sensitivity, specificity, positive and negative predictive values were adjusted for verification bias. HPV testing had a higher sensitivity (100%) and specificity (90.6%) compared to Pap cytology (sensitivity  =  78.2%; specificity = 86.0%) and VIA (sensitivity = 31.6%; specificity = 87.5%). Since 58% of the sample refused involvement and another 28% refused colposcopy or biopsy, we estimated that potentially 87.6% of the total underlying cases of CIN3 and cancer may have been missed due to program failures. We conclude that despite our use of available resources, infrastructure, and guidelines for cervical cancer screening implementation in resource limited areas, community participation and non-compliance remain the major obstacles to successful reduction in cervical cancer mortality in this Indian population. HPV DNA testing was both more sensitive and specific than Pap cytology and VIA. The use of a less invasive and more user-friendly primary screening strategy (such as self-collected swabs for HPV DNA testing) may be required to achieve the coverage necessary for effective reduction in cervical cancer mortality.

Amplicon sequencing has become a popular and widespread tool for surveying microbial communities. Lower overall costs associated with high-throughput sequencing have made it a widely adopted approach, especially for projects that necessitate sample multiplexing to eliminate batch effect and reduced time to acquire data. The method for amplicon sequencing on the Illumina HiSeq 2500 platform described here provides improved multiplexing capabilities while simultaneously producing greater quality sequence data and lower per-sample cost relative to those of the Illumina MiSeq platform without sacrificing amplicon length. To make this method more flexible for various amplicon-targeted regions as well as improve amplification from low-biomass samples, we also present and validate a 2-step PCR library preparation method. Amplification, sequencing, and analysis of the 16S rRNA gene affords characterization of microbial community composition. As this tool has become more popular and amplicon-sequencing applications have grown in the total number of samples, growth in sample multiplexing is becoming necessary while maintaining high sequence quality and sequencing depth. Here, modifications to the Illumina HiSeq 2500 platform are described which produce greater multiplexing capabilities and 300-bp paired-end reads of higher quality than those produced by the current Illumina MiSeq platform. To improve the feasibility and flexibility of this method, a 2-step PCR amplification protocol is also described that allows for targeting of different amplicon regions, and enhances amplification success from samples with low bacterial bioburden. IMPORTANCE Amplicon sequencing has become a popular and widespread tool for surveying microbial communities. Lower overall costs associated with high-throughput sequencing have made it a widely adopted approach, especially for projects that necessitate sample multiplexing to eliminate batch effect and reduced time to acquire data. The method for amplicon sequencing on the Illumina HiSeq 2500 platform described here provides improved multiplexing capabilities while simultaneously producing greater quality sequence data and lower per-sample cost relative to those of the Illumina MiSeq platform without sacrificing amplicon length. To make this method more flexible for various amplicon-targeted regions as well as improve amplification from low-biomass samples, we also present and validate a 2-step PCR library preparation method.

Multilevel stakeholder engagement in policy decision-making and implementation-planning is needed to build trust and deliver evidence-based health interventions.

Background Cervical cancer is a preventable cancer; however, decreasing its prevalence requires early detection and treatment strategies that reduce rates of loss to follow-up. This study explores factors associated with loss to follow-up among HPV-positive women after implementation of a new HPV-based screen-and-treat approach for cervical cancer prevention in Iquitos, Peru. Methods We conducted semi-structured interviews with “obstetras” (i.e., midwives) ( n  = 15) working in cervical cancer prevention and women ( n  = 24) who were recorded as lost to follow-up after positive HPV results. We used the Health Care Access Barriers Model to guide analyses. We utilized manifest content analysis to describe barriers to follow-up according to the obstetras and thematic analysis to report themes from the women’s perspectives. We also report the steps and time taken to contact women. Results We found an incomplete and fragmented patient monitoring system. This incomplete system, in conjunction with challenges in contacting some of the women, led to structural barriers for the obstetras when attempting to deliver positive results. Women in this study expressed a desire to receive treatment, however, faced cognitive barriers including a lack of understanding about HPV results and treatment procedures, fear or anxiety about HPV or treatment, and confusion about the follow-up process. Women also reported having important work matters as a barrier and reported frequently using natural medicine. Reported financial barriers were minimal. Conclusion This study highlights the barriers to follow-up after implementation of a primary-level HPV-based screen-and-treat approach. While some barriers that have previously been associated with loss to follow-up were not as prominently observed in this study (e.g., financial), we emphasize the need for screen-and-treat programs to focus on strategies that can address incomplete registry systems, structural challenges in results delivery, cognitive barriers in understanding results and treatment, and work-related barriers.

The species Alphapapillomavirus 7 (alpha-7) contains human papillomavirus genotypes that account for 15% of invasive cervical cancers and are disproportionately associated with adenocarcinoma of the cervix. Complete genome analyses enable identification and nomenclature of variant lineages and sublineages. The URR/E6 region was sequenced to screen for novel variants of HPV18, 39, 45, 59, 68, 70, 85 and 97 from 1147 cervical samples obtained from multiple geographic regions that had previously been shown to contain an alpha-7 HPV isolate. To study viral heterogeneity, the complete 8 kb genome of 128 isolates, including 109 sequenced for this analysis, were annotated and analyzed. Viral evolution was characterized by constructing phylogenic trees using maximum-likelihood and Bayesian algorithms. Global and pairwise alignments were used to calculate total and ORF/region nucleotide differences; lineages and sublineages were assigned using an alphanumeric system. The prototype genome was assigned to the A lineage or A1 sublineage. The genomic diversity of alpha-7 HPV types ranged from 1.1% to 6.7% nucleotide sequence differences; the extent of genome-genome pairwise intratype heterogeneity was 1.1% for HPV39, 1.3% for HPV59, 1.5% for HPV45, 1.6% for HPV70, 2.1% for HPV18, and 6.7% for HPV68. ME180 (previously a subtype of HPV68) was designated as the representative genome for HPV68 sublineage C1. Each ORF/region differed in sequence diversity, from most variable to least variable: noncoding region 1 (NCR1) / noncoding region 2 (NCR2) > upstream regulatory region (URR) > E6 / E7 > E2 / L2 > E1 / L1. These data provide estimates of the maximum viral genomic heterogeneity of alpha-7 HPV type variants. The proposed taxonomic system facilitates the comparison of variants across epidemiological and molecular studies. Sequence diversity, geographic distribution and phylogenetic topology of this clinically important group of HPVs suggest an independent evolutionary history for each type.