AIDS Research and Therapy

Extensive cervical lesion and treatment outcomes in women with HIV/HPV co-infection

Cervical cancer is a common cancer worldwide, with > 85% of deaths occurring in Lower- and Middle-Income Countries where resources for screening programs are limited. Women living with HIV (WLHIV) are at increased risk. HPV test-and-treat is a screening strategy where women with HPV are offered ablative treatment of the cervix to reduce the risk of invasive cancer. WLHIV tend to have more extensive cervical lesions, necessitating more specialised surgical treatments. ACTG A5282 was a randomised, open-label, Phase 2 trial conducted in seven countries that compared a cytology-based screening strategy to HPV test-and-treat for cervical cancer prevention in WLHIV. Women with cervical lesions inappropriate for ablative treatment were assigned to Arm C and underwent colposcopy and directed biopsies. Loop electro-excision procedure was performed if high-grade lesions (bHSIL) were present on cervical biopsies. Women were followed 26 weeks later for repeat evaluations. The Clopper-Pearson exact method was used to construct the 95% confidence interval for the proportion of WLHIV with lesions inappropriate for cryotherapy. Logistic regression models were used to assess the factors associated with these lesions. Of 1046 women screened, 156 (88%) were Black/Non-Hispanic, with a median age of 36 years; 80% were on ART, and 73% had an HIV-1 RNA < 200 copies/mL. On cervical colposcopy, 17% (179/1046, 95% CI 14.9-19.4%) had cervical lesions inappropriate for cervical ablation. Among 428 (44%) women with High-risk HPV (hrHPV) detected, 112 (26%, 95% CI 22.2%, 30.5%) had cervical lesions inappropriate for ablative therapy. hrHPV was found more commonly among women having lesions inappropriate for ablative therapy as compared to lesions appropriate for ablative therapy (70% vs 54%, p < .001). Among 128 women with extensive cervical lesions undergoing colposcopic biopsies, 43 (34%) had bHSIL detected. Among women undergoing LEEP treatment of bHSIL, 24% had bHSIL detected 26 weeks later. Cervical lesions inappropriate for ablative therapy were common among WLHIV. This has implications for cervical cancer programs as these lesions can only be optimally treated with surgical therapies such as loop electroexcision procedures, and the capacity for this procedure should be increased to maximise cervical cancer prevention outcomes.

HIV gp120/Tat protein-induced epithelial–mesenchymal transition promotes the progression of cervical lesions

Abstract Background Human immunodeficiency virus (HIV) infection is associated with an elevated incidence of cervical cancer, and accelerated disease progression, but the underlying mechanisms are not well understood. This study aimed to investigate the relationship between HIV infection and epithelial–mesenchymal transition (EMT) in cervical cancer. Methods Tissue samples from HIV-positive and negative patients with cervical intraepithelial neoplasia (CIN) and cervical cancer were analyzed for EMT-related proteins. Human cervical cancer SiHa cells were treated with HIV Tat and gp120 proteins to test their effects on EMT, migration, and invasion. Results HIV-positive patients had lower E-cadherin and cytokeratin, and higher N-cadherin and vimentin levels than HIV-negative patients. HIV Tat and gp120 proteins induced EMT, migration, and invasion in SiHa cells. Transcriptome sequencing analysis revealed that, compared to the control group, the protein-treated group showed upregulation of 22 genes and downregulation of 77 genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed the involvement of the Wnt signaling pathway in EMT. Further analysis of gene expression related to this pathway revealed upregulation of DVL1, TCF7, KRT17, and VMAC, while GSK3β, SFRP2, and CDH1 were downregulated. Immunofluorescence assay demonstrated that HIVgp120 and Tat proteins treatment induced elevated β-catenin expression with nuclear accumulation in SiHa cells. Conclusions The treatment of SiHa cells with HIV Tat and gp120 proteins induces EMT and activates the Wnt/β-catenin pathway, suggesting that the Wnt/β-catenin pathway may play a crucial role in promoting EMT progression in cervical lesion tissues of HIV-infected patients.

Should the management of high grade cervical squamous intraepithelial lesion (HSIL) be different in HIV-positive women?

Abstract Background This study compares the management and outcome of high grade squamous intraepithelial lesions (HSIL) in HIV-positive and -negative women and identifies risk factors for treatment failure. Methods This retrospective, controlled study includes 146 HIV-positive women, matched for HSIL, age and year of diagnosis, with 146 HIV-negative women. Differences were analysed using parametric and non-parametric tests and Kaplan–Meier survival curves. A binary logistic regression was used to assess risk factors for treatment failure. Results Persistence of cervical disease was observed most frequently in HIV-positive women (42 versus 17%) (p  &lt;  0.001) and the cone biopsy margins were more often invaded in HIV-positive-women than in HIV-negative ones. (37 versus 16%; p  &lt;  0.05). HIV-positive women, with successful cervical treatment had better HIV disease control: with significantly longer periods of undetectable HIV viral loads (VL) (19 versus 5 months; p  &lt;  0.001) and higher CD4 counts (491 versus 320 cells/mm3; p  &lt;  0.001). HIV-positive women with detectable VL at the time of dysplasia had 3.5 times (95% IC: 1.5–8.3) increased risk of treatment failure. Being treated through ablative therapy was associated with a 7.4, four-fold (95% IC: 3.2–17.3) increased risk of treatment failure compared to conization Conclusion HIV-positive women have a higher risk of treatment failure of HSIL than do HIV-negative women, especially when ablative therapy is used and in women with poor control of their HIV infection. The management and the follow- up of HSIL’s guidelines in this high-risk population should be adapted consequently: for HIV-positive women with uncontrolled viral load, excisional treatment should be the preferred therapy, whereas for women with undetectable viral load, CD4  +  lymphocytes higher than 500 cells/mm3 and with a desire of pregnancy, ablative therapy may be considered.