Human Papillomavirus (HPV) is an oncogenic virus that causes the highest number of viral-associated cancer cases and deaths worldwide, with more than 690,000 new cases per year and 342,000 deaths only for cervical cancer (CC). Although the incidence and mortality rates for CC are declining in countries where screening and vaccination programs have been implemented, other types of cancer in which HPV is involved, such as oropharyngeal cancer, are increasing, particularly in men. Mutational and transcriptional profiles of various HPV-associated neoplasms have been described, and accumulated evidence has shown the oncogenic capacity of E6, E7, and E5 genes of high-risk HPV. Interestingly, transcriptomic analysis has revealed that although a vast majority of the human genome is transcribed into RNAs, only 2% of transcripts are translated into proteins. The remaining transcripts lacking protein-coding potential are called non-coding RNAs. In addition to the transfer and ribosomal RNAs, there are regulatory non-coding RNAs classified according to size and structure in long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and small RNAs; such as microRNAs (miRNAs), piwi-associated RNAs (piRNAs), small nucleolar RNAs (snoRNAs) and endogenous short-interfering RNAs. Recent evidence has shown that lncRNAs, miRNAs, and circRNAs are aberrantly expressed under pathological conditions such as cancer. In addition, those transcripts are dysregulated in HPV-related neoplasms, and their expression correlates with tumor progression, metastasis, poor prognosis, and recurrence. Nuclear lncRNAs are epigenetic regulators involved in controlling gene expression at the transcriptional level through chromatin modification and remodeling. Moreover, disruption of the expression profiles of those lncRNAs affects multiple biological processes such as cell proliferation, apoptosis, and migration. This review highlights the epigenetic alterations induced by HPV, from infection to neoplastic transformation. We condense the epigenetic role of non-coding RNA alterations and their potential as biomarkers in transformation’s early stages and clinical applications. We also summarize the molecular mechanisms of action of nuclear lncRNAs to understand better their role in the epigenetic control of gene expression and how they can drive the malignant phenotype of HPV-related neoplasia. Finally, we review several chemical and epigenetic therapy options to prevent and treat HPV-associated neoplasms. In 2020, 19.3 million new cancer cases and 10 million deaths were estimated worldwide . About 1Recent data estimated that CC alone accounted for more than 600,000 new cases and more than 340,000 deaths . HPV infPapillomaviridae family, composed of 52 genera  studies describe a wide variety of HPV genotypes at various anatomical sites in both healthy tissues and malignant neoplasms. In 69% of healthy subjects, the presence of some HPV genotype has been identified, either in the intestine, mouth, skin, or vagina, being more frequent in the skin (61%) and vagina (41%) . In anogHuman papillomaviruses are epitheliotrophic species-specific viruses. HPV viral cycle is closely related to the differentiation of stratified squamous epithelium. About its genomic traits, HPV has a circular double-stranded genome of approximately 8,000 bp. In general, its genomic structure is composed of three regions: the early region (E), which encodes proteins responsible for the regulation of transcription and replication; the late region (L), which encodes structural proteins; and the long control region (LCR) or upstream regulatory region (URR). Transcription is polycistronic as in other viral species. In HPV16, the P97 and P670 promoters are the major transcription regulators. The P97 promoter controls the expression of the E6, E7, E1, E2, E4, and E5 polycistron in undifferentiated cells. The second promoter regulates the transcription of E1^E4, E5, L1, and L2 and is activated in differentiated cells . The genE1: This viral protein has the largest and most conserved ORF of the papillomavirus. The main function of E1 is to bind to the origin of replication to maintain viral replication and is responsible for maintaining the episomal state. E1 interacts with proteins of the replication machinery . Interestingly, it also interacts with Histone H1 to displace it from DNA. In addition, E1 has been shown to bind with epigenetic regulators such as HATs, HDACs, and SWI/SNF for chromatin remodeling .E2: E2 is a key regulatory protein encoded by all papillomaviruses. Interestingly, the short forms of splicing can act as repressors of E2. E2 can interact with specific viral DNA sequences, mainly methylation-dependent sequences, such as E2BS sites located within the LCR region. In addition, E2 is very important for the recruitment of E1 to the replication origin. E2 protein has a repressor role in E6 and E7 transcription, which has been associated with increased apoptosis and decreased cell proliferation , in partOn the other hand, E1 and E2 are known to be involved in the process of viral genome insertion into the host genome. However, only the E1 gene is involved in low-grade cervical intraepithelial lesions, and in high-grade lesions, the E1 and E2 genes are also disrupted. The hinge region of the E2 gene has been reported to be unstable making it possibly the most common break when HPV DNA integrates into the host genome . TherefoE2 functions as a histone code reader by interacting with the bromodomain containing 4 (Brd4) and interacting with acetylated histones in chromatin. E2 has been shown to bind to other chromatin regulators such as HAT (p300) HDAC 1, 2, and 3, KDM5C, SWI/SNF, TIP60, EP400, and SMCX .E8^E2: E2 splicing isoforms are transcribed from the promoter E8 located in E1. E8^E2 is a DNA-binding protein, which has been characterized as a transcriptional and viral replication repressor through the recruitment of the NCoR platform . This isE4: E4 localizes to the central region of E2 and is synthesized as a fusion protein of the E1^E4 transcript from promoter 8. E4 is the most abundant protein in the infected epithelium. This protein participates in amplification, release, and transmission of the viral genome. It also promotes the viral productive phase associated with epithelial differentiation-dependent post-translational modifications and participates in cytokeratins collapse and in G2 cell cycle arrest. It has been shown that E4 expression decreases as CIN grades increase until it disappears. E4 also correlates with low levels of methylation in the CADM1, MAL, or miR124-2 genes . These gE5: E5 is mainly localized in the intracellular membranes of the endoplasmic reticulum and Golgi apparatus. In these compartments, it binds with vacuolar ATPase to decrease endosomal acidification, which leads to the degradation of cell surface receptors. Studies have shown that E5 plays an essential role in carcinogenesis, as it is critical in cell transformation and immune modulation by interacting with the major histocompatibility complex class I (MHC-class I). In addition, this protein is involved in several biological processes such as differentiation-dependent viral cycle, DNA synthesis in supra-basal layers, viral amplification, and maintenance of the episomal state, and in the expression of late genes . E5 actiE6 y E7: One of the best described activities by HPV-HR proteins in the transformation process is the inactivation of the tumor suppressor genes p53 and pRB by E6 and E7, respectively . HoweverE6 is epigenetically regulated by CTCF and can generate distinct isoforms by splicing. Splicing products (E6*) antagonize the effect of full-length E6. E6 participates in immortalization, evasion of apoptosis, evasion of the immune response, the inhibition of the interferon response, participates in epigenetic reprogramming, and regulates chromatin structure through interaction with CBP and P300 .via Mi2β. E7 induces KDM6A and KDM6B expression, leading to host cell reprogramming by re-activation of HOX and p16INK4A genes. E7 also post-transcriptionally increases SETD2 levels and regulates H3K36me3 marks on viral chromatin  is specifically activated by E7 from HPV16 through the release of E2F. EZH2 is an enzymatic subunit that mediates H3K27me3 and contributes to cell proliferation (G1-S) involving several mechanisms such as the stimulation of Cyclin D1 and E, as well as retinoic acid signaling or the WNT pathway. In addition, EZH2 can suppress apoptosis through the silencing of the miRNA-31 promoter, which has among its regulatory targets the antiapoptotic gene E2F6 .Despite EZH2 increase by E6 and E7, the H3K27me3 mark does not increase; this is associated with the Ser21 phosphorylation, which is mediated by AKT. This modification prevents the methylation enzymatic activity while it increases the expression of histone demethylase KDM6A, associated with activation of HOX genes .Late ORF: L1 is the major capsid protein, which, can self-assemble into virus-like particles (VLP) and is mainly involved in the cell infection process. The L1 region of HPV is susceptible to DNA methylation which, interestingly, has been associated with lesion grade and viral integration. For example, methylation of CpG 5698 and 5617 is associated with high-grade lesions and CC .LCR: Regarding the LCR region, it is a viral sequence that does not encode proteins, but it is one of the most important regions of the virus since it contains the origin of replication and interacts with multiple epigenetic regulators and transcription factors. Comprising approximately 10% of the genome .Human papillomavirus DNA associates with proteins similar to H2A, H2B, H3, and H4 histones. Electron microscopy analyses revealed that the complete HPV genome contains 32 nucleosomes, each measuring about 12 nm in diameter . InteresChanges in chromatin are closely linked to the epithelial differentiation process. Viral promoters contact each other by three-dimensional folding of nucleosomes at different stages of the viral cycle. Some authors have proposed that chromatin modifications occur mainly in the proximal upstream regulatory region of E6 in undifferentiated cells, whereas in differentiated cells, it occurs in the late promoter region . HoweverInitially, when HPV infects undifferentiated cells of the basal layer of the epithelium, the viruses remain in an epigenetically repressed episomal state, with enrichment of H3K27Me3 and low levels of H3K4Me3. Consequently, there is a low viral load , which favors a deficient activation of the immune response .Chromatin immunoprecipitation assays on HPV31 revealed transcriptionally active chromatin marks such as acetylated H3K4me2 in HPV promoter regions p97 (early in LCR) and p742 (late in E7). Interestingly, these epigenetic marks increase after differentiation triggering E6/E7 transcription. In contrast, undifferentiated cells carry repressive marks such as H3K9me2 and H3K27me2 .Notably, the p97 promoter is regulated from the 5′ end in the LCR region; therein lies the origin of replication, the keratinocyte early enhancer (KE) and an auxiliary enhancer (AE) that enhances KE activation .Transcriptional activation marks recruit factors such as C/EBP-β and C/EBP-α to the LCR and late promoter sequences. Notably, the KE region is also an enhancer of the late promoter, so it has been proposed that differentiation alone might be enough to mildly induce late transcription without active viral replication  Figure .Some studies have shown that negative regulation of the HPV-16/18 E6-E7 promoter requires the binding of YY1 to the promoter KE sequence . YY1-dirHPV infection is initially established in undifferentiated basal cells, so there is no expression of E6 and E7. This transcriptional state is also dependent on CCCTC binding factor (CTCF). Studies in HPV 18 have described that CTCF can interact with the E2 ORF and, in turn, with YY1, whereby CTCF-YY1 mediates a three-dimensional interaction between the E2 ORF and the LCR region to establish a repressive chromatin loop . EpithelRecent findings have shown that viral integration events frequently trigger host chromatin changes, which enhance the carcinogenic process in HPV+ tumors. Interestingly, CTCF is a key regulator in these processes, since mutations that disrupt the binding sites as well as the introduction of new sites for CTCF can reorganize chromatin and modify transcriptional regulation, allowing tumorigenesis beyond the transcriptional regulation of E6/E7 . In addiStudies using C33a cells infected with HPV16 have revealed that the histone deacetylase sirtuin 1 (SIRT1) is recruited to the HPV replication origin to become part of the functional E1-E2 complex. Loss-of-function assays of SIRT1 by CRISPR-Cas9 showed increased replication of E1-E2 due to a growing stability of E2 caused by an increase in acetylation . InteresInterestingly, HPV31 E7 has been reported to increase SETD2 protein levels. SETD2 is a histone methyltransferase that writes the H3K36me3 mark (active transcription) on viral chromatin. SETD2 can collaborate in the viral cycle regulation by recruiting of H3K36me3 readers to HPV. Furthermore, experiments in CIN612 cells showed that SETD2 writes the H3K36me3 mark abundantly in E2, E4, and E5 ORFs and not in E6 and E7  Gautam .Likewise, the nuclear receptors have an essential role in viral chromatin regulation since they allow the recruitment of chromatin remodelers such as BRG1 and INI1 . These pThe first study to analyze viral DNA methylation, reported changes in the LCR with potential gene regulatory implications . SubsequSeveral authors have reported increased methylation in the L1 region associated with CIN3 or CC. Recently Bee et al. identified that methylation of the CpG 5615 site of L1 of HPV52 is most frequently associated with NIC3, and SNPs associated with the C clade . AdditioDiverse evidence has shown that patients with HNSCC may have different responses to treatment depending on HPV status, mainly due to transcriptomic changes involving genes related direct or indirectly by viral presence .The characterization of epigenetic alterations in neoplastic transformation is a significant event. Unlike genetic alterations, epigenetic changes are potentially reversible. Although the mechanisms that lead to epigenetic alterations are not fully understood, it is relevant that they could be used as diagnostic and prognostic biomarkers as well as therapeutic targets. This section will focus on some of the epigenetic alterations in precursor lesions and invasive cancer and their potential use as biomarkers.In contrast, Brennan et al. characterized five subtypes of HNSCC based on methylation profiles, one of them associated with HPV that corresponds to the previously described atypical expression profile and is associated with better survival . NakawagRecently, Comparing with normal tissue, 86 DMRs were identified in anal carcinoma and 36 in CC, of which 17 DMRs are shared in both malignancies  .Alternatively, different DMRs and differentially hydroxymethylated regions (DhMR) in genes involved in the Hippo pathway were identified in NIC 3 and CC. Interestingly, the number of DMR increases as the degree of injury progresses; however, the DhMRs decrease from NIC 3 to CC.Some genes from the DMRs were associated with survival  . GagliarGlobally, a greater number of methylated regions have been reported in HPV-positive cell lines and malignancies than in negative ones . HoweverIt is noteworthy that 30 MVPs were validated in independent cohorts in HNSCC and CC, managing to stratify the HPV+ cases from the negative ones according to epigenetic signature; additionally, significant differences were shown in survival at 5 years, in HNSCC (81% vs. 38%) and in CCSCC (77% and 50%), which was a better predictor of survival than the sole presence of HPV .In other PeSCC studies, 65 differentially methylated genes were identified, with inverse correlation with expression in HPV+ cases. Among which are CD70, HN1, FZD5, FSCN1, and PRR16 .The 5-hydroxymethylation of the cytokine (5hmC) associated with loss of transcriptional repression has been identified in lower levels in HPV + HNSCC compared to HPV- cases. Among the genes associated with hyper-5hmC in HPV+ tumors are CDKN2A and enrichment of pathway genes such as desmosomes, NF-kB, oxidoreductase activity, and mesenchymal cell differentiation where genes such as SNAI2, BMP2, SMAD2 and TGFB2 are found .Many cellular genes have been proposed as diagnostic and prognostic biomarkers in CC and its precursor lesions . Global Nowadays, the methylome offers several candidates with potential as clinical biomarkers and therapeutic targets in HPV+ neoplasms. In addition, non-coding RNAs have been highlighted in the scientific and therapeutic landscape. Interestingly, some ncRNAs are transcribed by the own HPV.The invention of new sequencing technologies, bioinformatics tools, as well as new experimental strategies, have made possible the discovery of new functional molecules of non-coding RNA (ncRNA) . It is wIn this section, we begin describing the HPV non-coding transcriptome, and finally, we highlight the function of lncRNAs induced by the viral oncoproteins in the host cell.Recent studies have shown that within the HPV genome, there are regions that contain circRNA and miRNA genes .CircRNAs are single stranded, covalently closed, circular RNA molecules. CircRNAs can be generated from several genomic regions . Regarding the biosynthesis of circRNAs, two biosynthesis models have been proposed, and both involve back-splicing .Although they have been little studied, there is evidence showing that they perform essential cellular functions. These molecules can act as miRNA sponges, or in some cases, they might indeed have coding potential, as is the case of circE7 . HPV16 cThere are few published studies regarding the miRNAs transcribed from the HPV genome. However, it has been shown that viral miRNAs modulate cellular and viral gene expression, promoting carcinogenesis and evading the host’s immune system. Shun-Long The predicted targets of HPV16-miR-1  are mainly involved with biological processes such as cell migration, cell motility, response to hypoxia, and regulation of cell adhesion. For HPV16-miR-3, the predicted targets  are associated with cell death, development, and cell differentiation . Regardiin situ hybridization in cervical tissue samples and cervical cell lines . Regarding the HPV16 viral genome, authors found four target sequences for HPV16-miR-H1-1, two in the E5 region and two in the L1 gene  Figure .HPV16-miR-H2-1 presented two targets in the viral genome, one in the LCR region and the other in the L1 gene . A gene Subsequent studies conducted by Elina Fringilla coelebs FcPV1 (fcpv1-miR-F1 and fcpv1-miR-F2)  . Interes-miR-F2) .The research field on miRNAs and cirRNAs encoded from HPV encourages new therapeutic strategies based on RNA for various medical applications. However, it would be essential to advance in greater depth in knowing the biological functions of these new molecules.LncRNAs are transcripts of more than 200 nucleotides long, which lack coding potential. LncRNAs have been classified in several ways, for example, according to their position concerning neighboring encoding genes   or accorLncRNAs acting as Decoys, induce or prevent proper regulation of gene expression through association with DNA-binding proteins. LncRNA scaffolds assemble various structural complexes to finally adapt them to specific transcriptional regulatory regions . LncRNAsStudies have shown that the presence of HPV in cancerous tissues stimulates the differential expression of lncRNAs. For example, Ma et al. found 107 differentially expressed lncRNAs when comparing normal tissue vs. HPV-negative HNSCC tumors. On the other hand, in the comparision of normal tissue vs. HPV-positive HNSCC, the number of lncRNAs with differential expression increased to 801 transcripts . FurtherIt should be noted that some studies have proposed lncRNAs expression signatures in cancer associated with HPV infection. However, the molecular mechanisms of action of these molecules have not yet been elucidated. Also, it is still unknown if these expression changes are an indirect consequence of viral infection or if ncRNAs and HPV oncoproteins directly regulate them.Viral proteins can alter the biological activities of lncRNAs either by binding to them directly or indirectly, thus changing their ability to interact with proteins or other nucleic acids . HPV, liInterestingly, lncRNAs have been found to enhance virus invasion and host cell reprogramming to allow sustained infection. Conversely, there are also antiviral lncRNAs that regulate the innate and adaptive immune response to eliminate viral particles. In the following section, we will detail some oncogenic and tumor suppressor lncRNAs that are regulated by E6 or E7 and that influence some features leading to malignancy  Ouyang .lncRNA SNHG8 -A recent study revealed that lncRNA SNHG8 is highly expressed in HPV-induced cervical cancer cells compared to HPV-negative cells . NotablylncRNA CCEPR -The Cervical Carcinoma Expressed PCNA Regulatory LncRNA (CCEPR) is highly expressed in cervical cancer . For thiCCEPR localizes in the nucleus, where it probably interacts with proteins and nucleic acids rather than modulating PCNA levels in the cytoplasm . NotablyLncRNA-FAM83H-AS1 -lncRNA FAM83H-AS1 is overexpressed in cervical cancer cells and HPV16-positive head and neck cancer cell lines compared to HPV-16-negative cells . NotablyLncRNA-FANCI-2 -It has been described that patients with aberrant expression of Fanconi anemia-linked genes have a high incidence of HPV-high risk-induced neoplasms. In a study by Haibin LncRNA-EBIC -In cervical cancer cells, the expression of E6 and E7 stimulates the expression of EZH2-binding lncRNA (lncRNA-EBIC), also known as TMPOP2 (Thymopoietin pseudogene 2) . MechaniThe function of lnc-EBIC in the presence of HPV viral oncoproteins has been recently investigated. Hongpeng Regarding the transcriptional regulation of lnc-EBIC, p53-responsive elements were found in its promoter region. ChIP studies have shown a decreased enrichment of p53 in the promoter region of this lncRNA in some types of cancer . In addiLINC01101 y LINC00277 -The function and mechanism of action of LINC00277 (known as EWSAT1) appear to be tissue specific. For example, in Ewing’s sarcoma, EWSAT1 is positively regulated by EWS-FLI1 in primary human pediatric mesenchymal progenitor cells, and its high expression correlates with increased cell proliferation . FurtherCRNDE -Studies by We believe that it would be essential to delve deeper into the regulation of the expression of these lncRNAs and their association with HPV, as they exert a very prominent role in cancer regulation. For example, lnc-CRNDE has multiple functions in the cell. For instance, it could function as ceRNA, RNA-decoy, scaffold and miRNA sponge in various types of cancer . Even lnAs for its mechanism of action, in cervical cancer CRNDE binds to PUMA, a modulator of apoptosis, to inhibit its expression. As a result, there is an increase in the expression of Bcl-xL, an anti-apoptotic protein that plays a crucial role in cell death . InteresFurther studies in cervical cancer by Lu Homo sapiens small nucleolar RNA host gene 12) has been studied in several types of cancer; however, studies by lncRNA-SNHG12 -The lncRNA-SNHG12 (LncRNA-DINO -Recent studies show that the Damage Induced lncRNA (DINO) is a 951 nucleotides long lncRNA located on chromosome six and divergently transcribed to the CDKN1A gene . SchmittInterestingly, it has been demonstrated that DINO expression is increased in cells expressing the HPV-16 E7 protein . It is aAdditionally, DINO expression presents a regulation mediated by epigenetic derepression (H3K27 demethylation) through KDM6A. In addition, in cervical cancer cells, it has been shown that DINO activation occurs through a pathway that is independent of ATM/CHK2 . Recent Studies by LncRNA-PRINS -To understand HPV-linked HNSCC progression, Magda Interestingly, the Psoriasis susceptibility-related RNA Gene Induced by Stress lncRNA (lnc-PRINS) was overexpressed in HVP (+) patients and was associated with better overall survival and disease-free survival. Lnc-PRINS expression levels correlate with antiviral response genes, e.g., CRTSS, TLR8, IRF5, CCL5, CD40, NOD, CARD9, PYCARD, PSTPIP, and IFNAR1. In addition, lnc-PRINS modulates gene expression of transcripts involved in the inflammatory response, growth factors, proinflammatory genes, chemokines, and immunostimulators among others, so lnc-PRINS may stimulate the immune response of patients with HPV + HNSCC . Some stDNA methylation status has been proposed in CC screening programs as a triage strategy for women with positive HPV results and cases with atypical squamous cells of undetermined significance (ASCUS). If not diagnosed and treated on time, the HPV persistent infection can generate precursor lesions that become cervical cancer. For this reason, once HPV+ cases have been identified in the screening programs, a second test (triage) should be carried out to differentiate between cancer precursor lesions that could potentially progress (persistent infection) from those that do not (transient infection). At this second triage, determining DNA methylation of a group of cellular or viral genes has enormous diagnostic utility for HPV (+) cases.Initial studies postulated the methylation of CADM1 and MAL to detect cervical intraepithelial neoplasia (CIN) 2 and 3, being more sensitive as a triage strategy than cytology . MethylaAmong the clinical studies that validate methylation profiles as biomarkers of CIN2, CIN3, and CC, is the S5 trial. S5 evaluates the methylation of EPB41L3 and the late region of HPV16, −18, −31, and −33 with a sensitivity of 74% and a specificity of 90% . AdditioSubsequent studies confirmed the usefulness of EPB41L3, SOX1, and HS3ST2 as a triage method for HSIL detection . StudiesTwo panels of methylation markers to detect CIN2+ have been validated in the Dutch and Chinese populations (C13ORF18/EBP41L3/JAM3 y C13ORF18/ANKRD18CP/JAM3). These assays showed a sensitivity of 79% and 76% and a specificity of 57% and 65%, respectively . Other sFurthermore, long-term studies (14 years) showed that the cumulative incidence of CC in HPV+ samples is higher using FAM19A4 and miRNA-124 methylation profiles compared with a positive cytological result as a triage strategy . This asRecent studies show that the FAM19A4/miR124-2 assay performed better than HPV16, 18, 31, 33, and 45 genotyping in HPV-positive women with borderline or moderate dyskaryosis, ASC, or LSIL, since the absolute risk of CIN3+ was higher (33%) than with other methods. Interestingly, combining the FAM19A4/miR124-2 assay with HPV16/18 increased detection by 40%. This strategy would allow more significant differentiation of patients with CIN3+ . AdditioOther miRNAs such as miR-15b-5p and miR-375 have been evaluated together with FAM19A4, and this approach manages to distinguish CIN3 cases . In addiin situ detection , CONFIDENCE Marker (POU4F3), and CERVI-M (PAX1) . PAX1, ietection .A meta-analysis identified the DNA methylation of CADM1, MAL, MIR-124-2, FAM19A4, POU4F3, EPB41L3, PAX1, SOX1, and L1/L2 from HPV16 as a triage strategy for HPV-AR+ cases .These studies indicate that in CC, the HPV test and triage based on DNA methylation, identify with higher specificity and sensitivity, healthy vs. precursor lesions. All those methylation biomarkers validated, could be extended to other HPV (+) neoplasms to early detection.The dynamic and reversible nature of epigenetic modifications makes them ideal therapeutic targets for treating HPV-associated cancers. Several studies have analyzed the effect of epigenetic therapies and chemopreventive agents in both cell lines and HPV+ neoplasms, including CC and HNSCC.The potential of different natural compounds derived from plant sources such as phytochemicals has been evaluated as chemopreventive or adjuvants in anticancer therapies for several neoplasms. Exploring the potential therapeutic use of these compounds is particularly important since there are no specific treatment strategies for HPV + HNSCC.in situ , a polyphenol found in the rhizome of curcuma plants, has been reported to inhibit the transcription of E6 and E7, thus restoring the expression of p53, pRB, and PTEN . In CC cThe FDA has approved several HDAC inhibitors as therapeutics with anticancer potential. Accumulating evidence has demonstrated that HDAC inhibitors are helpful for the treatment of hematological malignancies such as multiple myeloma and leukemia. Meanwhile, the efficiency of HDAC inhibitors in solid tumors is currently being assessed.In vitro assays show that HDAC inhibitors such as sodium butyrate and trichostatin A can reverse the HPV-induced proliferation. These inhibitors neutralize the viral oncoproteins, increasing p21 and p27 expression, resulting in the Cyclin-dependent kinases suppression activity, arrest in the G1 phase of the cell cycle, and therefore, p53-independent and p73-dependent apoptosis is induced  attenuates side effects provoked by HDAC inhibitors . AnotherRegarding the combination of HDAC inhibitors with antivirals to eradicate HPV infections, hitherto, there are no HPV-specific antiviral agents approved for clinical use, however, machine learning and therapeutic repositioning are emerging strategies to identify antiviral molecules. In addition, HDAC inhibitors have been used in combination with other drugs that block the activity of immune checkpoint proteins, for example, Chidamide is a benzamide that selectively suppresses the activity of class I and class IIb HDACs, increasing the acetylation of histones H3/H4, thus promoting transcription. Chidamide is currently in phase Ib/II clinical trials (NCT04651127). This inhibitor sensitizes advanced and metastatic, persistent, or recurrent cervical cancer tumors for further treatment with PD-1 inhibitors to boost the immune response against cancer cells.In transformed follicular lymphoma, chidamide impacts on the PI3K-AKT pathway  and in lPEVO trial evaluates the response to the combination of pembrolizumab and vorinostat, HDAC inhibitor, in several tumors recurrent and metastatic squamous cell carcinomas, HPV+ vs. HPV−. This study might provide clues to determine how HPV presence influences tumors’ therapeutic response and could also identify predictive and pharmacodynamic biomarkers .Other therapies include the epigenetic factor DNMT. 5-azacytidine and decitabine are drugs approved by the FDA to inhibit DNMTs for myelodysplastic syndrome and acute myeloid leukemia treatment. In HPV + solid tumors, has been evaluated the potential of these drugs as monotherapy or in combination with chemotherapy or immunotherapy.In murine models and clinical trials in HNSCC HPV+ patients (NCT02178072), the 5-azacitidine treatment decreases proliferation, expression of viral genes, the activity of metalloproteases and induces p53-dependent apoptosis . In anotAn additional epigenetic factor of great relevance is EZH2. Since EZH2 is more expressed in HPV+ OPSCC tumors than in HPV− cases , there aThe epigenetic effects of chemopreventives and therapeutic agents in HPV-associated neoplasms are still a subject of study from a functional and clinical perspective.Unlike genetic alterations, epigenetic alterations are potentially reversible. Epigenetic, systemic or targeted therapy is an area with great potential for the treatment of several neoplasms. These therapies must be directed according to the biological characteristics of tumor, in order to provide the greatest benefit and reduce adverse effects. Epigenetic alterations are a tool for monitoring therapeutic responses. The control of neoplasms associated with HPV is a feasible challenge to achieve since there are prophylactic vaccines, screening, and triage methods, which are focused on cervical cancer, however, in other neoplasms these strategies can also have an impact favorable. The discovery of epigenetic alterations induced by HPV, and new viral non-coding RNAs and methylation signatures, opens the possibilities for their application as triage biomarkers, and for designing drugs to modify the epigenetic landscape for improved patient survival and quality of life based on comprehensive treatments.


The burden associated with schizophrenia is substantial. Impacts on the individual, healthcare system, and society may be particularly striking within the veteran population due to the presence of physical and mental health comorbidities. Disease burden is also influenced by a complex interplay between social determinants of health and health disparities. The objective of the current study was to compare non-healthcare societal outcomes between veterans with and without schizophrenia in the United States Veterans Health Administration (VHA).A retrospective cohort study was conducted using the VHA database . Veterans with schizophrenia  were identified; the index date was the earliest observed schizophrenia diagnosis. Veterans with schizophrenia were propensity score-matched to those without schizophrenia using baseline characteristics. A 12-month baseline and variable follow-up period were applied. The frequency of unemployment, divorce, incarceration, premature death, and homelessness were compared between the matched cohorts using standardized mean difference (SMD). Risk of unemployment and homelessness were estimated using logistic regression models.A total of 102,207 veterans remained in each cohort after matching . Among veterans with schizophrenia, 42% had a substance use disorder and 30% had mental health-related comorbidities, compared with 25 and 15%, respectively, of veterans without schizophrenia. Veterans with schizophrenia were more likely to experience unemployment , divorce , homelessness , incarceration , and premature death  than veterans without schizophrenia. After further adjustments, the risk of unemployment and of homelessness were 5.4 and 4.5 times higher among veterans with versus without schizophrenia. Other predictors of unemployment included Black [per AMA] race and history of substance use disorder; for homelessness, younger age (18–34 years) and history of mental health-related comorbidities were additional predictors.A greater likelihood of adverse societal outcomes was observed among veterans with versus without schizophrenia. Given their elevated risk for unemployment and homelessness, veterans with schizophrenia should be a focus of targeted, multifactorial interventions to reduce disease burden. Schizophrenia is a severe mental health disorder, affecting more than 23 million individuals globally, including approximately 3 million people in the United States (US) . SchizopThe economic burden associated with schizophrenia in the US has increased over the past decade . The oveThe burden of schizophrenia may be particularly pronounced in younger patients because they are at increased risk for poor treatment adherence and disease relapse , 18–20. While the substantial burden of schizophrenia has been well-documented in the general US population, to the best of our knowledge, there is no literature describing societal outcomes within the US Veterans Health Administration (VHA) population, among whom the prevalence of mental health disorders, including schizophrenia, is high relative to the general population . TherefoVHA is the largest integrated healthcare system in the US, providing health services to more than 9 million veterans. Clinical and administrative data were extracted from the integrated databases of the VHA Corporate Data Warehouse. This included VHA’s electronic medical records, which capture information from inpatient, outpatient, and ED visits for all persons treated within the VHA, as well as the VHA Vital Status files, which contain demographic and mortality information obtained from multiple VHA and non-VHA sources .All study procedures were carried out in compliance with federal and institutional ethical guidelines. The Veterans Affairs Central Institutional Review Board (IRBnetID: 1478231–1) provided approval for this study on December 17, 2019. The requirement to obtain informed consent from study participants was waived because the Institutional Review Board deemed this study to involve no more than a minimal risk to the privacy of individuals. Data used in the study were de-identified, and only aggregated results were shared.We conducted a retrospective matched cohort study using the US VHA data from January 1, 2013 to September 30, 2019 (study period). Two cohorts of veterans were identified: the schizophrenia cohort and the non-schizophrenia cohort. Both cohorts included veterans aged 18 years and older who were enrolled in VA benefits for at least 12 months  and clinical characteristics, including history of substance use disorder (identified by ≥1 record of ICD-10 codes F10.x–F19.x and/or corresponding ICD-9 codes [303.x–305.x]), Charlson Comorbidity Index (CCI), comorbidities of interest , and self-reported Patient Health Questionnaire-2 (PHQ-2) scores were assessed during the 12-month pre-index period for each cohort. The PHQ-2 contains questions about the frequency of depressed mood and anhedonia over the past 2 weeks; scores range from 0 to 6, with a score of 3 or higher considered the optimal cut-point when using the PHQ-2 to screen for depression  . DiagnosMortality outcomes included death, age at death, and frequency and causes of premature death during the variable follow-up period. Premature death was defined as death < 80 years old based on the definition used by the Centers for Disease Control and Prevention . Cause oVeterans in the schizophrenia cohort were 1:1 propensity score matched to veterans in the non-schizophrenia cohort to ensure the balance of baseline demographic and clinical characteristics; greedy nearest neighbor matching without replacement  was used. Given the large sample size for the non-schizophrenia cohort, a representative sample of 500,000 veterans without schizophrenia meeting the inclusion and exclusion criteria were considered for matching. The propensity score model included age, sex, race, geographic region of residence, urban vs. rural residence, index year, and CCI. The matched cohorts were considered well-balanced for a given variable if the absolute standardized mean difference (SMD) between the cohorts was 0.1 or less. Additionally, young veterans (aged 18–35 years) with schizophrenia were similarly matched to young veterans from the non-schizophrenia cohort.All study measures were summarized using descriptive statistics. For descriptive analyses, categorical measures were reported as frequency and percentage, and continuous variables were described as mean, standard deviation (SD), first quartile, median, third quartile, minimum, and maximum. The matched cohorts were compared using SMD, with any value of 0.1 or greater considered statistically meaningful. Data were analyzed using SAS version 9.4 .The risks of unemployment and homelessness were compared between the schizophrenia and non-schizophrenia cohorts using logistic regression models, adjusting for age group, sex, race, geographic region of residence, mental health-related comorbidities, substance use disorder, and CCI. Only 2 of the 4 non-healthcare societal burden measures  were further adjusted for these covariates because of the SMDs observed post-matching and because improvements in unemployment and homelessness have been associated with positive effects on health outcomes for patients with schizophrenia –28. OddsAfter matching, 102,207 veterans remained in each of the cohorts  were similar to the overall schizophrenia cohort, except for the younger age at index  and higher frequency of mental health-related comorbidities ; the odds of homelessness were 5.1 times (95% CI: 4.78–5.55) greater in the young veterans with versus without schizophrenia. In this model, young veterans with history of substance use disorder had 2.4 times greater odds of homelessness compared with veterans without history of substance use disorder.The mean (SD) follow-up time was 4.2 (1.8) years for the schizophrenia cohort and 3.8 (1.9) years for the non-schizophrenia cohort. Of the veterans who died during the observable follow-up , the average age at death was 69 years for the schizophrenia cohort and 74 years for the non-schizophrenia cohort (SMD: − 0.42). A total of 83.4% and 61.7% of the veterans who died in the schizophrenia and non-schizophrenia cohorts, respectively, were considered to have died prematurely (SMD: 0.07). The 3 most common causes of premature death among veterans with schizophrenia were cardiovascular disease (15.1%), cancer (14.0%), and chronic lower respiratory disease (5.6%). Substance abuse (2.8%) and intentional self-harm  ranked within the top 10 causes of premature death.Overall, our findings are consistent with the literature and highlight the significant burden of schizophrenia among veterans utilizing VHA services. The study population was predominantly male, White veterans in their 50s–60s; similar to previous studies on US veterans with schizophrenia or schizoaffective disorder , 30. Vetn = 4903) multiplied by the estimated annual cost of sheltering an unhoused individual  [Although our study did not evaluate costs and causality cannot be confirmed, our findings of societal outcomes may potentially infer substantial associated economic burden. For example, the number of veterans with schizophrenia who experienced homelessness in the present study   yields a$18,668) , 40, andIn addition, a subset of young veterans with schizophrenia was evaluated in this study because they were expected to be at an early stage of the disease, a time at which patients are at greater risk of relapse due to poor adherence to medications and, hence, have a greater disease burden –20. Our Our study also found a more frequent occurrence of premature death among veterans with schizophrenia, with 14.2% meeting our criteria for premature death compared with 11.9% of veterans without schizophrenia. Furthermore, the mean age of death was 69 years in veterans with schizophrenia, 5 years younger than that for veterans without schizophrenia. This finding is consistent with a large survey of veterans, in which those with schizophrenia died earlier of heart disease than those with no mental health disorder diagnoses (68.6 years vs. 76.5 years) , and witOur findings emphasize the need for early interventions in patients with schizophrenia, including non-pharmacological and pharmacological interventions aimed at preventing relapse, reducing hospitalization, and managing comorbidities such as mental health and substance use disorder. For example, the literature suggests a positive impact of non-pharmacological interventions such as vocational services along with psychotherapy or housing services on health outcomes , 27; theTo our knowledge, our study is the first to evaluate the frequency of non-healthcare societal outcomes in schizophrenia in the US veteran population. Strengths of our study include utilization of the VHA database which provided a large sample size, long follow-up period , and access to societal measures not typically available in administrative claims and electronic medical records data. The database also allowed for a more comprehensive view of patient journey and health care receipt; veterans are less likely to seek care for mental health outside of the VHA system due to limited private providers of veteran-focused health services . In addiDespite these strengths, there are several limitations of this study. Given that the study population is limited to veterans obtaining health care through the VHA system, the study findings may not be generalizable to the general US population. For example, women in particular were substantially underrepresented. The VHA population has been reported to have particularly high prevalence of mental health conditions, including substance use disorder and PTSD, when compared to the general US population . MoreoveFurthermore, our study data did not capture costs; therefore, we did not quantify the cost of outcomes we examined. Future studies quantifying the cost of outcomes we measured are also warranted. Lastly, the divorce rate in the schizophrenia cohort may be underestimated because it was not assessed among veterans with schizophrenia who were married; the marriage rate among veterans with schizophrenia was lower than in the non-schizophrenia cohort.In this population of patients treated in the VHA system, greater likelihood of adverse non-healthcare societal outcomes were observed among veterans with schizophrenia versus without schizophrenia. Given their elevated risk for unemployment and homelessness, veterans with schizophrenia should be a focus of targeted, multifactorial interventions to reduce disease burden.


After the diagnosis of L-SIL, 77. 3% had a persistent infection and anomalous Pap Test results. Many of these patients had highlighted psychological consequences such as anxiety, hypochondria, fear of cancer, and sexual problems. Several studies suggested that the clearance of HR-HPV infection could be accelerated by cervical excisional procedures, especially in L-SIL. In consideration of the psychological implications for HPV infection and related dysplasia in patients with CIN1 at PAP-smear and HR-HPV positivity at least for 6 months, we decided to plan a prospective study where we tried to anticipate excisional cervical using a minimally invasive treatment: thin loop electrosurgical excision procedure (t-LEEP). This study aims to analyze the clearance of HR-HPV after 6 and 12 months, clinical outcomes related to t-LEEP, and the psycho-relational impact at 12 months after t-LEEP.We enrolled patients with the diagnosis of L-SIL at PAP-smear and HR-HPV positivity with a persistent CIN 1 (at least for 6 months), confirmed by cervical biopsy. All enrolled patients underwent t-LEEP. We followed prospectively and performed for all patients the HPV DNA test at 6 (T1) and 12 months (T2) and STAI-Y and FSFI scores at T0 and T2.We prospectively enrolled 158 patients, 22 are excluded for the established criteria. Patients with HR-HPV and CIN 1 lesions treated with t-LEEP had an overall clearance of 83.8% at T2. In subgroups analysis at T2, we had a regression: in smoker 71.8%, in contraceptive users 69.5%, in patients aged <25 years 100%, aged 25–30 years 85%, aged 30–35 years 94.4%, aged 35–40 years 92%, and aged ≥40 years 89.1%, in HPV-16 96.4%, in HPV-53 89.5%, in HPV-18 87.5%, in HPV-31 86.6%, and in coinfected 3.5%. STAI-Y and FSFI after t-LEEP (T2) were statistically significant, reducing anxiety status and improving sexual function.Based on these results, the use of t-LEEP in patients with persistent CIN 1 and HPV-HR at least for 6 months could be useful for accelerating HPV-HR clearance, in particular, for a subpopulation patient with an increased risk of progression and/or patients with psychological and sexual consequences of carrying an HR-HPV infection. High risk–human papillomavirus (HR-HPV) infection is associated with cervical intraepithelial neoplasia and its persistence is considered essential for the progression of cervical precancer to invasive cervical cancer (CC) , 2. The CIN grade 1 is a common cervical precancer, especially in young women who are sexually active. CIN 1 cervical precancer, often, has an overlap with low-risk HPV (LR-HPV) infection. In a recent study in the literature based on 2 years of follow-up data after diagnosis of low-grade cervical lesions with prior low-grade cytology, it was found that 22.7% of the patients experienced cytologic regression in the first year. Persistently altered cytology to PAP-smear was valued as 77.3% at 1st year of follow-up, in particular among women aged > 35 years, regression rates were lower than in younger people with an average persistence of ~80% after 28.8 months of follow-up . The recSeveral studies in the literature suggested that clearance of high-risk HPV infection could be accelerated by cervical excisional procedures especially in low-grade cervical lesions, thus quickly eliminating the main factor of development of cervical cancer .Thin loop electrosurgical excision procedure (T-LEEP) is a modified surgical treatment for cervical lesions , in which a minimal amount of cervical tissue is excised using electrosurgery with no impact on pregnancy outcomes and minimal adverse effects .In consideration of the psychological implications of HPV-related dysplasia in these patients such as anxiety, avoidance of sexual intercourse with their partner, or delay in the pregnancy planning, we decided to plan a prospective study where we decided to anticipate excisional cervical treatment using t-LEEP at 6 months in all patients with persistent HPV HR-related dysplasia confirmed by cervical biopsy at 6 months. Our study aims to analyze the clearance of HR-HPV in different populations after 6 and 12 months, clinical outcomes related to t-LEEP, and the psycho-relational impact at 12 months after t-LEEP.We evaluated for the enrollment of all patients referred to the Departments of Obstetrics and Gynecology and Gynecologic Oncology, Campus Bio-Medico University Hospital of Rome with a cytological diagnosis of Low-Grade Squamous Intraepithelial Lesion (L-SIL) at cervical Papanicolaou (Pap) smear and HR-HPV positivity with a persistent CIN 1 (at least for 6 months), confirmed by cervical biopsy. Inclusion criteria for enrolment were as follows: (1) age between 16 and 70 years; (2) histological diagnosis of CIN 1 persistent for at least 6 months confirmed by colposcopically-directed cervical biopsy; (3) detection of HR-HPV preoperatively on a cervical or vaginal swab; (4) LSIL at Pap-smear; and (5) informed consent obtained from the patients. Exclusion criteria included the following: (1) HIV or immunosuppression; (2) history of chronic illness; (3) pregnant or minimum of 6 months postpartum; (4) treatment for cervical disease or abnormal cytology within 18 months. For each patient enrolled, we recorded the following: age, menopausal status, smoking status, the desire of pregnancy, parity, utilization of combined oral contraception (COC), and previous cervical surgical procedure.All enrolled patients underwent different questionnaires to examine anxiety state and sexual function after enrollment (T0).State-Trait Anxiety Inventory for Adults, Form Y-1 (STAI-S): It measures state anxiety and consists of 20 items; STAI is a validated test for measuring preoperative anxiety , 15. We Female Sexual Function Index (FSFI): It measures the female sexual functions and consists of 19 items. It has been developed for the evaluation of female sexual arousal disorder (FSAD) with six domains of sexual function: desire, arousal, lubrication, orgasm, satisfaction, and pain .All enrolled patients underwent t-LEEP under deep sedation. T-LEEP is a surgical treatment for cervical lesions, in which a coin-shaped  of cervical tissue is excised using electrosurgery . All tisThe HPV clearance rate was evaluated for all patients enrolled at T1 and T2: we performed a subgroup analysis based on age, HPV genotype, utilizers of combined oral contraceptives (COC), and smoking status. HPV reinfection rate and mean time clearance were also calculated; therefore, we compared the results of STAI-Y and FSFI preoperatively (T0) and post-operatively (T2) for all patients included in the study, and then, we performed a subgroup analysis in cleared and non-cleared patients.p < 0.05 was considered statistically significant.This study was conducted following the regulatory standards of Good Clinical Practice and the Declaration of Helsinki (1996) and was approved by the institutional review board. An exploratory descriptive analysis of patient's characteristics and main outcomes was performed. The distributive normality of the data was evaluated through the Shapiro–Wilk test. We analyzed the data related to sexual function and psychological function using the robust two-way mixed ANOVA test, evaluating the relationship between the scores obtained in the various questionnaires, clearance, and clearance time. All tests were evaluated with a 95% significance level, and a Between January 2015 and December 2019, we selected 158 patients referred to the Departments of Obstetrics and Gynecology and Gynecologic Oncology, Campus Bio-Medico University Hospital of Rome with a cytological diagnosis of Low-Grade Squamous Intraepithelial Lesion (L-SIL) at cervical Pap-smear and HR- HPV positivity with a persistent CIN 1 (at least for 6 months), confirmed by cervical biopsy. Of these, 5 were excluded for the presence of previous cervical treatment within 18 months and 17 were affected by chronic illness . At the end of enrollment, 136 patients were included in this study . The meaAll patients consequently underwent t-LEEP under deep sedation. The mean thickness of the specimen of t-LEEP was 3.6 mm (range 1–10 mm), with a medium length of 14.8 mm (range 3–20 mm) and a medium width of 9.5 mm (range 2–18 mm). Histological examination of the t-LEEP specimen showed 132 patients with a diagnosis of CIN 1 (97%) and 4 patients with a diagnosis of CIN 2 (3%), and margins of the histological specimen were free from cervical dysplasia . These pPost-operative complications were classified by Cleaven-Dindo classification. Only 11 patients (8%) reported Grade-1 complications  and no patients reported worse complications .The cumulative overall clearance rate of HPV-HR infection at T1 and T2 was 96 (70.5%) and 114 (83.8%), respectively. The total persistence at T1 and T2 was 29.5% and 16.2%, respectively .In subgroup analysis, we found that clearance rate is differently correlated with the genotype of HPV. In fact, the clearance at T1 was 91.1% for HPV16, 84.2% for HPV53, 69% for HPV 18, 66% for HPV31 60% for other types of HR HPV, and 1% for coinfected patients with different serotypes of HPV. This ratio increased at T2: 96.4% for HPV16, 89.5% for HPV53, 87.5% for HPV18, 86.6% for HPV31, 90% for other types of HR HPV, and 3.5% for coinfected patients with different genotype of HPV .n = 70/97). At T2, the clearance rate of smokers was 71.8% (28/39) compared to 87.6% (85/97)  and of the 97 non-smoking patients was 72.2% ( (85/97) .n = 64/90). At T2, the clearance rate of COC users was 69.5% (32/46) compared to 87.9% (80/91) in non-users patients  and of the 90 patients users of non-COC was 71.1%  in patients aged <25, 70% (14/19) in patients aged 25–30, 77.8% (14/18) in patients aged 30–35, 60 % (15/25) in patients aged 35–40, and 73.3% (44/64) in patients aged ≥40 and a regression rate at T2 of 100% in patients aged <25 (10/10), 85% (17/19) in patients aged 25–30, 94.4% (17/18) in patients aged 30–35, 92% (23/25) in patients aged 35–40, and 89.1% (57/64) patients aged ≥40 .p < 0.0001) with a global reduction of anxiety status.Following cervical dysplasia diagnosis, we submitted the STAI-Y questionnaire to the 136 patients enrolled at T0. The main STAI-Y score at T0 was 58.4; we submitted the same form of STAI Y-20 at T2: the mean score decreased to 43.0 significatively (p < 0.00001).We performed therefore a subgroup analysis, and we observed that in cleared patients, mean STAI-Y T0 score was 59.2 and the T2 score was 40.0. The mean overall difference between T2 and T1 was 19.1 with a significant improvement in anxiety status (p = 0.18) with a persistent anxiety status. There is a significant two-way interaction between clearance status and time (p < 0.001). Moreover, we found a significant main effect in time (p < 0.001)  .p < 0.0001) with a significant improvement of sexual function. We performed therefore a subgroup analysis, and we observed that in cleared patients, mean FSFI T0 score was 22.7 and the T2 score was 27.7. The FSFI score significatively increased (p < 0.00001), and it was superior to the cutoff indicated to define “sexual dysfunction” (<26.55). In non-cleared patients, mean FSFI T0 score was 26.4 and the T2 score was 25.2. At T2 mean score decreased but the difference between scores at T0 and T2 was non-statistically significant (p = 0.23) with a slight reduction of sexual function. There was a significant two-way interaction between clearance status and time (p < 0.001). Moreover, we found a significant main effect in time (p < 0.001)  .During the 12-month follow-up, we collected collateral information on obstetric outcomes of patients undergoing t-LEEP. The result was: 62 had a desire for offspring after surgery (44.5%), 10 pregnancies occurred (in the study period), in 8 (80%) of which no adverse reactions were reported. The mean gestational age at birth was 39 + 2 weeks. None of them were hospitalized with a risk of preterm birth or threat of miscarriage. Two abortions occurred, one in the sixth week and the other in the eighth week of gestation. No obstetric outcomes beyond 12 months were reported in the study.Our study aims to analyze the clearance rate of HR- HPV and clinical outcomes in women who have been treated by t-LEEP with histology of persistent CIN 1 (at least 6 months) confirmed by biopsy, and psycho-relational impact related to HPV clearance. The transformation zone is the one most susceptible to HPV infection and therefore predisposed to precancerous transformation with different degrees of dysplasia. It is characterized by metaplastic tissue, where there is a transition between the exocervical squamous epithelium that continues in the vaginal lining and the glandular tissue of the endocervix . This isSo far, there is no reliable method to distinguish progressing from non-progressing CIN, therefore, neither validated medical nor conservative treatments for HPV infection: thus, the only validated treatment at this time remains surgical treatment that appears to be unpredictable for many patients. In our study, we propose to anticipate the cervical excisional treatment to clear rapidly HPV infection, thus avoiding psychological consequences related to HPV infection itself.*1301 seems to have a protective role in the pathogenesis of cervical cancer  DRB1l cancer , 20. HPVl cancer .A good spontaneous regression rate of L-SIL cervical dysplasia is reported in the study by Moscicki et al. ranging from 61% at 12 months to 91% at 36 months .In a cohort study of 44,102 women, the overall type-specific HR-HPV clearance rates in patients with borderline/mild dyskaryosis at 6- and 18-month clearance rates were 29 and 41% . HolowatA systematic review of the literature that analyzed 24 studies worldwide with comparative data for 16,573 patients with CC and 35,509 without CC showed that there is an increased relative risk of CC in patients who use COCs and a decrease in relative risk after the cessation of the latter. Then, 10-year use of COCs cumulative incidence of invasive CC is estimated to increase from 3.8 to 4.5% in more developed countries and 7.3 to 8.3% in developing countries .Kreimer et al. performed a study on 481 women infected with HPV, and the study reports that after LEEP, the regression rate of HPV infection is 74% for patients with HPV16, 81% for patients with HPV18, and a higher regression rate for infection of other HPV genotypes at 6 months of follow-up . HR-HPV Our study proposes to anticipate cervical excisional treatment at 6 months to clear rapidly HPV cervical infection; our data are comparable to data of the literature: cervical excisional treatment could accelerate HPV clearance with an overall clearance rate of 70.1% at 6 months and 83.2% at 12 months compared to spontaneous clearance rate that is around 30–50%. In particular, the proportion of cleared patients increases in subpopulations in which spontaneous clearance is usually reduced such as age > 35 years, smoker patients, and users of oral contraceptives.Moreover, t-LEEP could be a low harming treatment with a very low percentage of complications. In our study, we showed only 8% classified as grade 1 and no major complication by Cleaven-Dindo Classification in 137 patients enrolled in the study. For the treatment of precancerous cervical lesions, both ablative methods  and LEEP excisional methods, cold cone) can be used effectively. Common complications of these procedures reported in the literature, including minor vaginal bleeding in the first 24 h after surgery which was 5.7% for cold cone, 5.4% for LEEP, 0.4% for cryotherapy; minor vaginal bleeding 24 h after surgery which was 8.3, 8.8, and 23.7% for cold cone, LEEP, and cryotherapy, respectively; cervical stenosis ; pain  .Although several studies have concluded that cervical excision procedures were associated with an increased risk of preterm birth, especially as excision depth increases, with a relative risk of 2.15 for excisional treatment >1.0 cm –37, otheDue to the sexually transmitted nature of HPV, psychosocial effects of HPV-linked diseases and abnormal cytology results have been demonstrated in the literature. The previous studies showed that even positive screen results for HPV might have psychosocial consequences. These effects could include a reduction of sexual desire or sexual satisfaction, feeling sexually unattractive, sexually anxious, or depressed . McCaffeClarke et al. performed a study of 489 HPV-positive men and women, reporting that at the time of diagnosis of infection, the most frequent feelings were depression, anger, isolation, fear of rejection, shame, and guilt .The psychological distress experienced by the patient was not limited to the screening test and HPV diagnosis to the screening test but extends to the other aspects that were corollary to this infection, such as fear of recurrent gynecological visits, apprehension of passing on HPV to your sexual partner and thus be negatively judged by the latter . All of Maggino et al. performed a study where on a group of 72 patients and how the diagnosis of HPV affects their quality of life and immediately after the moment of diagnosis, reporting how patients who tested positive for HPV had a higher level of anxiety, obsessions, compulsions, hygiene concerns, and other possible unlikely infections . An impaThe stigma of having an STI sometimes may negatively impact sexual self-image  and may affect sexual spontaneity or alter sexual activities , 47, 48.Our study confirms that early clearance of HPV can improve the anxiety status of patients (shown by the significant improvement of the score of the questionnaire administered), thus improving the quality of life. Therefore, the awareness of an HPV-HR infection, with a greater risk of evolution toward a CC, would seem to have a negative role in reducing sexual desire. The different studies in the literature have shown a negative effect on sexual function after HPV infection. In a study of 72 patients tested for HPV, there were no significant differences in sexual satisfaction between women HPV positives and women HPV negatives after a follow-up of 6 to 12 months following HPV result . ConcernIn our study, we found a better overall anxiety status and a better sexual function after cervical treatment with a statistically significant result. In subgroup analysis, it also analyzed anxiety status and sexual function in HPV-cleared patients and HPV-non-cleared patients. In our study, we found a significant decrease of anxiety status in HPV-cleared patients shown by the reduction of STAI-Y score after cervical treatment. Similarly, we found a better sexual function in cleared patients: FSFI score increased in cleared patients after treatment with a mean score of 27.74 representatives of normal sexual function, superior to the optimal cutoff score for differentiating women with and without sexual dysfunction (mean score >26.55) . In non-In our study, we found that anticipating surgical cervical treatment at 6 months of persistent CIN 1 related to HR HPV could be a valid alternative to conservative treatment. In our study, we demonstrated that t-LEEP is a low harming treatment with only a few post-operative complications; t-LEEP can also accelerate clearance of HR-HPV with a CIN 1 lesions at 6 and 12 months with a clearance rate superior to spontaneous clearance as reported in the literature: in patients at greater risk of progression and low possibility of spontaneous regression such as aged > 35 years, smokers, contraceptive users can benefit from early cervical treatment. Patients who benefited from early cervical treatment with consequent viral clearance showed an improvement in their state of anxiety and their sexual function and therefore a better quality of life.Based on these results, the use of t-LEEP in patients with persistent CIN 1 and HPV-HR at least for 6 months could be useful for accelerating HPV-HR clearance, in particular, for a subpopulation patient with an increased risk of progression and/or patients with psychological and sexual consequences of carrying an HR-HPV infection.We suppose that t-LEEP could not greatly impact pregnancy outcomes due to a limited cervical tissue excised. Although pregnancy outcomes need further investigations, we could propose t-LEEP to patients who have already satisfied pregnancy desires and mentioned risk factors for dysplasia progression.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Gynecology Campus Bio-Medico. The patients/participants provided their written informed consent to participate in this study.FP, GR, FF, CD, RM, FG, DL, SF, RA, and CT: substantial contributions to conception and design. FP, GR, FF, SF, and CT: drafting and revising the article critically for important intellectual content. FP and FF: final approval of the version to be published. All authors read and approved the final version of the manuscript and have contributed to the protocol/project development, data collection, management, data analysis, and manuscript writing and editing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer SL declared a past co-authorship with the authors to the handling editor.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Little research has been conducted to explore variables associated with the healthcare providers’ (HCPs) understanding and recommendation of human papillomavirus vaccine (HPV) since the vaccine was approved for use in China.A large-scale cross-sectional survey was conducted in southern China covering Guangdong, Guangxi, and Hainan provinces between April 2019 and October 2019. Firstly, descriptive analysis was used to access awareness, knowledge, barriers, and recommendations toward HPV vaccine among all participants. Multi-variable logistic regression was further applied to explore potential factors associated with awareness, acknowledgment of HPV vaccine, and recommendation behaviors toward HPV vaccine.OR = 1.18, 95% CI 1.13–1.23).2075 questionnaires were collected, and 2054 were included in the final analysis. In total, 77.9% of participants have heard of HPV vaccine and obtained sub-optimal HPV/HPV vaccine knowledge scores with a mean (SD) of 13.8 (3.5) out of a maximum score of 23. 68.1% HCPs reported that they have recommended HPV vaccine to others. Province and profession were the most significant characteristics associated with awareness, knowledge score, and recommendation behavior toward HPV vaccine. HCPs in Guangdong obtained a much better knowledge score [Mean (SD) = 15.5 (3.0)] and reported higher recommendation behavior (82.8%). Compare with HCPs from the Division of Expanded Program on Immunization (DEPI), Community Health Center (CHC), and obstetrician-gynecologists, other non-HPV closely related professions showed a less competent knowledge of HPV and HPV vaccine [Mean (SD) = 12.5 (3.0)] and lower frequency of recommendation behavior on vaccination (58.1%). The difference in HPV vaccine knowledge among different professions was concentrating on the items about clinical pathology of HPV and the practical aspects of HPV vaccine. Educational level and title were also closely associated with their knowledge of HPV and its vaccine. Besides, knowledge scores independently determined with recommendation behavior (Knowledge level of HPV and HPV vaccine as well as recommendation behavior toward HPV vaccine were relatively lower in southern China and differed significantly between provinces. Profession-specific gaps on the knowledge level of HPV and HPV vaccine emphasized the need for targeted education and training to improve HCPs’ engagement in the promotion of the HPV vaccine.The online version contains supplementary material available at 10.1186/s12905-022-01728-8. Cervical cancer is the fourth most common gynecological cancer and causes a tremendous disease burden in China , 2. ChinHPV vaccine has been proved efficacy for protecting against HPV-related diseases and decreasing the corresponding disease burden –8. AfterHealthcare providers (HCPs) play a significant role in HPV vaccine uptake because their recommendations, reminders, or/and counseling for the vaccine are associated with attitude toward vaccine among the general population and parental intention to vaccinate their children –18. FurtMost studies investing HPCs’ knowledge and attitude toward HPV vaccine targeted to whole HPCs or single profession but few stratified by different professions. In current healthcare practice in China, Community Health Center (CHC) is the main unit for primary health care including implementing the vaccination service. The Division of Expanded Program on Immunization (DEPI) affiliated to Chinese Center for Disease Control and Prevention (CDC) takes the primary responsibility for leading immunization activities including technical guideline formulation, surveillance as well as health education and public communication of vaccination. Obstetrician-gynecologist in hospital provided therapeutic services for relative HPV-related diseases. Thus, HCPs from the DEPI affiliated to CDC, HCPs from CHC, and obstetrician-gynecologist in hospitals are three major professions directly responsible for public HPV vaccine recommendation or inoculation. Other non-HPV closely related HCPs also need to discuss HPV and HPV vaccine queries during patients’ clinic visits. As HPV vaccine obtained more attention in recent years, the discrepancy of knowledge and recommendation toward HPV vaccine between different professions need to be analyzed for further targeted education to overcome vaccine confusion and hesitancy among HCPs and audiences.For bridging the knowledge gap mentioned above, the present study aimed to assess awareness, knowledge of HPV and HPV vaccine as well as recommendation behavior toward vaccination among HCPs with different professions in southern China. Furthermore, other associated potential factors like demographic characteristics were also investigated and analyzed.A cross-sectional survey of awareness, knowledge, and recommendation toward HPV vaccination for HCPs from Southern China  was administered between April 2019 and October 2019. Randomized cluster sampling was used to select 17 cities/counties from 39 cities/counties. A target sample size of 2000 was predetermined based on the ability to estimate an HPV awareness rate of 50% ± 1.5% with 95% precision.Data were collected and managed using Research Electronic Data Capture (REDCap), an electronic data capture tool hosted at Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College , 23. REDThe questionnaire was developed by a research team consisting of epidemiologists, HCPs from DEPI, and gynecologists based on information from previous studies conducted by the research team . The drat-test or analysis of variance (ANOVA). Multi-variable logistic regression analyzed factors  associated with: (1) Awareness of HPV vaccine; (2) knowledge score of HPV and HPV vaccination among respondents who have heard of HPV vaccine; (3) HPV vaccination recommendation behavior  among respondents who have heard of HPV vaccine. Odds ratios (OR), 95% confidence intervals (95% CI), and P-values were calculated for each independent variable. Twotailed tests with P values less than 0.05 were thought to be statistically significant. Analyses were performed using R software, version 3.5.2.The socio-demographic information was summarized by descriptive statistics. HCPs were divided into four groups according to professions: HCPs from DEPI, HCPs from CHC, obstetrician-gynecologist, and other HCPs. HCPs from DEPI, HCPs from CHC and obstetrician-gynecologist were HCPs work closely with HPV vaccination. Other HCPs included healthcare providers from non-immunization division of CDC, non-obstetrician-gynecologist clinicians, nurses, and researchers in hospitals. Awareness of HPV vaccine, knowledge score of HPV and HPV vaccine, HPV vaccination recommendation behavior were presented with frequency and percentage. The difference in awareness and recommendation of HPV vaccination between subgroups were compared using Chi-square tests while the difference in knowledge score was compared using In total, 2074 questionnaires were collected, and 20 were excluded after checking for missing information and logistic errors. A total of 2054 records were included in the final analysis. A summary of the socio-demographic characteristics of the respondents was provided in Table OR = 0.35, 95% CI 0.11–0.87) showed significantly lower awareness of HPV vaccine. Other variables significantly associated with awareness of HPV vaccine were province , the minority , educational level  and title  in multi-variate logistic regression.Most participants reported that they had heard of HPV vaccine , but awareness differed by province, age, ethnicity, education level, profession, and title Table . CompareIn total, the mean (SD) of HPV and HPV vaccine knowledge among the participants who have heard of HPV vaccine was 13.78 (3.45), with a mean (SD) of HPV knowledge was 6.61 (2.15) out of a maximum score of 14 and mean (SD) of HPV vaccine knowledge was 7.14 (1.98) out of a maximum score of 9. The proportion of correct responses to knowledge items were shown in Additional file OR = 0.12, 95% CI 0.08–0.18; Hainan: OR = 0.28, 95% CI 0.16–0.48), master and higher education level , other HCPs  and Associate senior/Senior  , male, Han, HCPs from DEPI, master and above and Associate senior/Senior group obtained a higher knowledge score of HPV and HPV vaccine. The result of multivariate linear regression showed that variables associated with HPV and HPV vaccine knowledge score were province  were willing to recommend HPV vaccine to others The most important reason why respondents were unwilling to recommend HPV vaccine to others was that they worry about the safety of HPV vaccine , old age , other HPCs , knowledge score of HPV and HPV vaccine   reported that they have recommended HPV vaccine to others, and 91.1% HCPs from DEPI have recommended. Factors associated with HPV vaccination recommendation behavior included province  in southern China. In general, awareness, knowledge level, and recommendation behavior were relatively lower in southern China and differed significantly among the three provinces. Besides, the present study also found that profession was a key predictor of HCPs’ awareness, knowledge, and recommendation behavior toward HPV vaccine.In the present study, around 77.9% of HCPs had heard of HPV vaccine in southern China, lower than the rate in mainland China according to the previous study (84%) . Among tThe knowledge score of HPV vaccine items was quite high while the score of HPV items was relatively low. According to the correct rate of each knowledge item, more than 90% HCPs have acknowledged that HPV effect can cause cervical cancer, HPV vaccine can prevent cervical cancer and cervical screening is needed after HPV vaccination, but most HCPs have less understanding of HPV, especially classification of HPV types. The result indicated that most HCPs only simply understood the HPV and were aware of the benefits of HPV vaccine but had no depth-understanding of the clinical pathology of HPV. Research conducted in countries with HPV vaccination programs also revealed that knowledge about HPV and the HPV vaccination among health professionals was frequently incomplete, and the lack of complete knowledge had the potential to spread misinformation and cause confusion among patients , 25, 26.Compare with other HCPs, the knowledge scores of HPV and HPV vaccine were significantly higher in HCPs from DEPI and CHC and obstetrician-gynecologist. Though other HCPs were not the dominant role in introducing or recommending HPV vaccine, they would run into some consultation for HPV vaccine during the clinic. Due to the late approval and unavailability in the NIP, the current HPV vaccine uptake in China is far from optimistic. A nationwide survey showed that the HPV vaccine uptake rate of females aged 18–45 was only 3% . FurtherThe difference in HPV and HPV vaccine knowledge among different professions was concentrating on the items about clinical pathology of HPV and the practical aspects of HPV vaccine such as risk factors of HPV infection, classification of high and low-risk types, the meaning of valent, and the best time for HPV vaccine. It was not hard to explain that other HCPs had insufficient knowledge on both HPV and HPV vaccination. Compared with HCPs from CHC, obstetrician-gynecologist obtained a relatively high correct rate of HPV knowledge items but not for the HPV vaccine knowledge items. Previous studies also found that HCPs worked at general and specialist hospitals had a lower understanding of HPV vaccine while providers who worked at community health service centers achieved significantly higher knowledge scores for HPV vaccine than other HCPs, which might be attributable to the HPV vaccination policies in China . ConsideRegarding the recommendation practice toward HPV vaccine, it was not surprising that other HCPs reported lower recommendation behavior compared with HCPs from DEPI, CHC and obstetrician-gynecologist. In China, HCPs from DEPI and CHC work directly related to HPV and HPV vaccine for DEPI affiliated to CDC takes the primary responsibility for leading immunization activities while CHC is the main unit for implementing the vaccination service. Obstetrician–gynecologist have more opportunities to make HPV vaccination recommendations due to clinic consulting. By contrast, other HCPs have fewer opportunities to recommend HPV vaccine. Another independent variable associated with recommendation behavior was knowledge of HPV and HPV vaccine. Higher knowledge could increase the confidence of HCPs in presenting and discussing the HPV vaccine . We alsoThe HPCs’ awareness differed highly between provinces, with 94.2% HPCs having heard of HPV vaccine in Guangdong but only 67.4% in Guangxi and 86.3% in Hainan. In terms of the knowledge score of HPV and HPV vaccine, far more HCPs from Guangdong province achieved higher knowledge scores compared with Guangxi province and Hainan province. One possible reason for this discrepancy was that awareness and understanding toward HPV vaccine might be associated with medical resources and the level of medical treatment of each province. It is acknowledged that the medical level in Guangdong is superior to the other two provinces, and could be certified according to China’s hospital rankings . BesidesIn terms of education level and title, a higher education degree or higher title could predict HCPs’ awareness of HPV vaccine and a higher knowledge level of HPV and HPV vaccine. Considering over half of HCPs in Southern China have a degree lower than master or have a title lower than associate senior, organizing regular internal training sessions and developing education packages about HPV are necessary to facilitate HCPs with accurate knowledge and recent progress. More HCPs with high education levels and high titles reported that they have recommended HPV vaccine to others, but education degree and title were not the independent variables for recommendation behavior mostly contributed to HCPs’ profession.There were several limitations in our study. Firstly, the present study was cross-sectional and the data collection was based on self-reported data, which might be subject to self-reporting bias and a tendency to report socially desirable responses. A second limitation was that participant in the survey was purely voluntary, it was hard to avoid nonresponse bias. The majority of participants in the present study were females, which may be due to females having more attention to HPV vaccine than males. Though the gentle distribution in the present study may overestimate the result, it reminded us that the importance of targeted education to provide adequate information HCPs. Third, the questionnaire was developed from previous studies , 33. HowIn this large-scale survey, we concluded that awareness, knowledge level, and recommendation behavior were relatively lower in southern China and differed significantly between provinces. Profession-specific knowledge gaps on the understanding of HPV and HPV vaccines reflected some phenomenon or shortage of current situations of HPV and HPV vaccination in southern China, which provided evidence for further vaccine roll-out activities. As knowledge level of HPV and HPV vaccines is an important key associated with recommendation behavior, more targeted education is necessary to provide adequate information HCPs for increasing HPV vaccine uptake.Additional file 1. Fig S1. Correct responses to HPV and HPV vaccine knowledge items(N=1601). Fig S2 Barriers forward willingness to recommend HPV vaccination.


In the Lao People's Democratic Republic (Lao PDR), cervical cancer is the third leading cause of women cancer.careHPV™ test versus conventional Pap smear or Siriraj liquid‐based cytology in the detection of cervical cancer in women living with human immunodeficiency virus type 1 (HIV‐1).The objective of this cross‐sectional study was to compare the efficacy of careHPV™ test, and HPV‐16 genotyping. The exact McNemar test was used to compare the efficacy and diagnostic performance of the tests.Overall, 631 women consented to participate. Four cervical specimens were taken for the purpose of conventional Pap smear, Siriraj liquid‐based cytology, careHPV™ test was higher  than that detected by conventional Pap smear . careHPV™ and HPV‐16 genotyping had, respectively, the highest sensitivity  and specificity . HPV‐16 was the most frequently detected genotype.Of the 631 women with follow‐up, 331 were human papillomavirus (HPV) negative. High‐grade squamous intraepithelial lesions were found in 37 women, biopsy‐proven high‐grade cervical intraepithelial neoplasia in 50 women, and invasive carcinoma in seven women. The proportion of women with high‐grade cervical lesion or carcinoma detected after abnormal careHPV™ test represents a screening option in Lao PDR, particularly in women living with HIV‐1 because of higher prevalence of chronic HPV in this population. LaoCol study provided health authorities in Lao People's Democratic Republic with a basis for improving their national cervical cancer screening policy and some epidemiological information useful for the establishment of a possible human papillomavirus vaccine prevention policy. Overall, 70% of cervical cancers are due to persistent infection with human papillomavirus (HPV) oncogenic genotypes 16 and 18.careHPV™ test, based on signal amplification of HPV DNA, allows the detection of 14 high‐risk genital HPV (HR‐HPV) genotypes and presents several advantages over the standard molecular techniquescareHPV™ test on cervical specimens, p = 0.0163).To prevent cervical cancer, the World Health Organization (WHO) provided recommendations for a screen‐and‐treat program.Infection with human immunodeficiency virus type 1 (HIV‐1) increases the risk of developing precancerous and cancerous cervical lesions.In Lao PDR, the prevalence of HIV‐1 infection is relatively low, around 0.2% in 15–49 years old.Regular screening is considered as a key tool in the prevention of cervical cancer, in particular in women living with HIV‐1 for whom the primary prevention by vaccination is not effective.Attending HIV treatment centers could be an opportunity to screen for cervical cancer. The most successful strategy for cervical cancer screening, the conventional Pap smear test, that has shown to help reducing the cervical cancer rates by 60%–90% in developed countries, relies on a level of infrastructure unattainable in most of the developing world. In the past few years, several tests looking for the DNA of HR‐HPV have demonstrated high sensitivity in the detection of cervical intraepithelial neoplasia (CIN).2careHPV™ test versus conventional Pap smear or Siriraj liquid‐based cytology in the detection of histology proven high‐grade CIN or invasive cervical cancer in a cohort of women living with HIV‐1 in Lao PDR.The main objective of this cross‐sectional study was to compare the efficacy of careHPV™ and PapilloCheck HPV test, (3) to determine the prevalence of different types of oncogenic HPV strains among women living with HIV‐1, and (4) to identify factors associated with CIN grade 2 and plus (CIN2+).The secondary objectives were (1) to estimate and compare the performances  of these three tests in the detection of histology proven high‐grade CIN or invasive cancer (CIN2+), (2) to assess the agreement between the two cytological tests and between 33.1The study population included women living with HIV‐1 who attended four HIV reference centers in Lao PDR in Vientiane , Savannakhet and Luang Prabang from January 2014 to May 2015 and who consented to participate.Eligible women had documented HIV‐1 positive status, were aged between 25 and 65 years, and had no history of cervical cancer, pelvic radiotherapy, or recent pregnancy (until 3 months after delivery). The study protocol and consent forms were approved by the Lao PDR Ethical Review Committee  and the Thailand Ethical committee . All participants provided written informed consent.Previous medical history, the most recent CD4 cell count, HIV viral load, and current cART medication were collected from the patients' medical record.careHPV™ collection medium for HPV testing using careHPV™ (QIAGEN); and (4) with a cytobrush placed into PapilloCheck® collection medium for HPV genotyping using PapilloCheck®. Physical examination included a systematic colposcopy; acetowhite areas were biopsied and processed for histological examination. Patients with positive HR‐HPV DNA and negative colposcopy were proposed a gynecologic follow‐up 6 months later.Gynecological examination was performed in all participants by the same gynecologist. Four cervical specimens were collected from each patient: (1) with a spatula for conventional pap smear cytology; (2) with a cytobrush placed into a plastic vial containing a specific preservative solution for Siriraj liquid‐based cytology; (3) with a cytobrush placed into Appropriate free of charge treatment was provided to patients identified with CIN lesions or cancer.3.23.2.1Systematic colposcopy and histological examination of biopsies carried out in women with abnormal colposcopy were considered as the reference method to determine the presence of high‐grade cervical lesions or cancer. Absence of high‐grade lesions was defined as normal colposcopy or absence of high‐grade lesions (CIN2 and CIN3) and carcinoma by histological examination.In patients with normal colposcopy and one abnormal cytological test , a second colposcopy was performed to re‐evaluate the presence of high‐grade cervical lesions or cancer.3.2.2Both cervical cytology tests were evaluated, regardless of the HPV results. The results were categorized according to the 2001 Bethesda System terminology3.2.3careHPV™ test (Qiagen), a signal‐amplification diagnostic test allowing the detection of 14 HR‐HPV genotypes .Specimens collected for HPV DNA testing were stored at room temperature and sent to the Centre d’Infectiologie Christophe Mérieux  High‐risk HPV detection was performed within 14 days after sampling using the ® test system . The test can identify 24 HPV genotypes including HPV6, 11, 16, 18, 31, 33, 35, 39, 40, 42, 43, 44/55, 45, 51, 52, 53, 56, 58, 59, 66, 68, 70, 73 and 82.Specimens collected for the identification of specific HPV genotypes were kept at −20°C and sent by batches to the virology laboratory at Chiang Mai University on a monthly basis. HPV DNA genotyping was performed using the PapilloCheck3.2.4careHPV™), and an expected proportion of discordant pairs of 2.7%. Based on these parameters, the requested sample size to detect a significant difference with a unilateral alpha risk of 5% and power of 80% was 600 patients .The sample size was estimated to compare the efficacy of two screening tests, measured by the proportion of women detected with a high‐grade lesion (CIN2+) among the screened women. We assumed an expected difference of 1.7% in the proportion of detected women between the two screening tests , positive likelihood ratio (LR+), negative likelihood ratio (LR−), and their 95% confidence interval (CI) were estimated based on the Wilson Score method. The level of agreement for cytology interpretation between conventional Pap smear and Siriraj liquid‐based cytology was estimated after classification into two categories: negative or minor cytological abnormalities  versus significant cytological abnormalities . The agreement between the http://www.r‐project.org).All statistical analyses were carried out using the R software, version 3.3.1  cells/mm3. At inclusion, 94.2% of women were on cART, with a median CD4+ cell count of 374 (IQR: 240–504) cells/mm3 and median HIV load of 4341 copies/ml . Of the 501 women with known results, 471 (94%) had HIV load <200 copies/ml.Table 4.2Overall, 631 women had a follow‐up, of whom 222 (35.2%) were HPV positive Figure . At leas4.3careHPV™ test as compared to conventional Pap smear or Siriraj liquid‐based cytology in the detection of cervical cancer is shown in Table careHPV™ test was significantly higher  than that detected by conventional Pap smear . The efficacy of careHPV™ versus Siriraj liquid‐based cytology and PapilloCheck versus careHPV™ was not significantly different.The efficacy of TMcareHPV had the highest sensitivity  while HPV‐16 genotyping showed the lowest sensitivity . The best specificity was seen for HPV‐16 genotyping . careHPV™ and liquid‐based cytology had similar ability to confirm and eliminate the presence of CIN2+ histology lesions with a LR+ of 2.6 and a LR− of 0.3. Sensitivity and specificity of each test stratified by age group are provided in Table careHPV™ and Siriraj liquid‐based cytology showed 100% sensitivity in women more than 50 years old while the specificity did not vary between the age strata. The accuracy of each test in terms of the proportion of true positive and false negative is reported in Table Performance of different techniques to detect CIN2 or higher grade lesions is shown in Table With cytology diagnoses classified into two categories: negative or minor cytological abnormalities  versus significant cytological abnormalities (ASC‐H and HSIL), the agreement between conventional Pap smear and Siriraj liquid‐based cytology was poor .4.4HPV genotypes detected by PapilloCheck are presented in Figure careHPV™ and PapilloCheck HPV test assessed at aggregated level for 14 HPV high‐risk types in 591 specimens was moderate  (Table The agreement between 6) Table .4.5careHPV™ test  and presence of HPV‐16  were significantly associated with CIN2+ lesions. Multivariate analysis with HPV‐16 in the model showed that nadir Lymphocyte CD4 account less than 200 cells per mm3 was significantly associated with a decreased risk of CIN2+ in HIV‐1–infected patients .Factors associated with CIN2+ lesions in HIV‐1–infected women are summarized in Table 5careHPV™ test versus conventional Pap smear or Siriraj liquid‐based cytology in the detection of cervical cancer in a cohort of women living with HIV‐1 in Lao PDR. The results showed that the efficacy of careHPV™ test to detect high‐grade cervical lesions or carcinoma was significantly higher than the conventional Pap smear but was not significantly different than that of Siriraj liquid‐based cytology. However, as the careHPV™ molecular test does not have an internal control to assess the sampling error, we cannot consider samples negative for high‐risk HPV as true high‐risk HPV negative samples.The primary objective of this cross‐sectional, multicenter study was to compare the efficacy of All women were examined and underwent colposcopy and biopsy by the same gynecologist. We found high prevalence of HR‐HPV (34.8%), similar to what has been reported in a study of women living with HIV‐1 in Thailand,Cytology, either conventional Pap smear or Siriraj liquid‐based cytology, visual inspection with acid acetic and HPV testing are the current screening tests for cervical cancer and pre‐cancerous lesions, with large disparities in their access worldwide. Cervical cytology Pap smear test is the most common screening method, established in high‐income countries as the primary screening test, and has led to significant decrease in the incidence of and mortality from cervical cancer.Siriraj liquid‐based cytology was developed to improve the diagnostic reliability of conventional Pap smear. Siriraj liquid‐based cytology rinses cervical cells in preservatives so that blood and other potentially obscuring material can be separated. The rate of detection for epithelial cell abnormalities was similar using either conventional Pap smear or Siriraj liquid‐based cytology in some studiescareHPV™ for a single‐visit screen‐and‐treat approach can increase the screening intervals.careHPV™ test to detect CIN2+ lesions were, respectively, 80.8% and 68.5%. HPV‐16 genotyping was the less sensitive (25.2%) but as reported elsewhere,careHPV™ test has been evaluated in other settings among women in the general population. In a cross‐sectional study among women attending routine cervical cancer screening in Tanzania, the sensitivity and specificity of the careHPV™ test to detect high‐grade cervical lesions or cancer (HSIL+) were 88.9% and 78.9%, respectively.careHPV™ testing was the most sensitive and had the best NPV for CIN2+ and CIN3+ as compared to vaginal careHPV™ testing, visual inspection with acetic acid, or conventional pap smear.careHPV™ was higher than the conventional Pap smear but almost equivalent to Siriraj liquid‐based cytology. The relatively low accuracy of careHPV™ could result in more false‐positive results and over‐referral for colposcopy.Molecular tests for the detection of HPV DNA can increase the sensitivity to detect CIN2+ lesions, thereby improving the prevention of cervical cancer. Different molecular assays for HR‐HPV detection in primary screening for cervical cancer prevention have provided a significant increase in sensitivity and reproducibility compared to the conventional Pap smear test.careHPV™ test represents an attractive screening option for the screen‐treat approach recommended by the WHO. It could also replace the need for colposcopy examination which can be limited in developing countries due to the lack of expertise or equipment.Given its clinical performance and affordable cost, careHPV™ test has been evaluated in rural China in the general population of women aged 25–65 years of age and was shown to be comparable to the gold standard HPV test Hybrid Capture 2 (HC2).careHPV™ was 41.9% and the sensitivity of the test to detect CIN2+ was 80.8%, almost similar to those of 93.3% and 94.3% observed in two studies performed among women living with HIV‐1 in Africa.careHPV™ in the present study (68.5%) was higher than that (58%) reported in the Segondy et al. study.Women infected with HPV‐16 and/or HPV 18 are more likely develop CIN2 or worse lesions than those infected with other high‐risk genotypes.As in other parts of the world, epidemiological studies in Southeast Asia have shown that the distribution of cervical HPV genotypes differs across populations, and oncogenic genotypes other than HPV‐16 and HPV‐18 are frequent.careHPV™ on self‐collected vaginal samples or clinician‐collected cervical samples.To further increase the screening rate, self‐collected vaginal samples were used in a study carried out in slums of Hyderabad.careHPV™, was designed specifically, and approved by the WHO, for application in low‐resource public health settings to screen women 30 years of age and older. The test procedure is simpler than other assays and has a faster time to results. Therefore, this test represents an attractive screening option in Lao PDR and similar countries. This is particularly true for women living with HIV‐1 because of the higher prevalence of chronic HPV infection in this population. The implementation of information campaigns and screening programs in HIV attending centers would be a significant step toward the set‐up of such programs at national level. This project was the opportunity to strengthen the skills of Laotian healthcare actors who received additional training on screening, diagnosis, and treatment of cervical cancer.Cervical cancer screening requires a sensitive and specific test. However, the highly trained personnel and sophisticated laboratory equipment needed to achieve this level of performance are often lacking in developing countries. The results of LaoCol study can be used by local health authorities as a basis to improve their national cervical cancer screening policy and to establish HPV vaccination programs.Supplementary MaterialClick here for additional data file.