Syndemic Synergy of HPV, HIV, and HSV-2 for Oncogenic HPV Replication in Female Sex Workers

Abstract

Background: Female sex workers (FSWs) in sub-Saharan Africa bear a disproportionate burden of sexually transmitted infections, including HIV, high-risk HPV (HR-HPV), and herpes simplex virus type 2 (HSV-2). This study evaluated possible association between HR-HPV, HIV, and HSV-2 among FSWs in the Democratic Republic of the Congo.

Methods: A cross-sectional study was conducted among 432 FSWs (mean age, 28.1 years) recruited via respondent-driven sampling. Genital self-sampling using the V-Veil UP2™ device was performed, followed by HPV genotyping and quantification by multiplex PCR, and HSV-2 DNA detection by PCR.

Results: Among 415 participants, HR-HPV prevalence was 36.9%, with HPV-52 (14.9%), HPV-58 (10.1%), and HPV-16 (6.5%) as leading genotypes. Overall, 89% of HR-HPV-positive women harbored genotypes covered by Gardasil-9^®. Co-infection with HIV and HSV-2 significantly increased HPV prevalence, genotype diversity, and viral load. Notably, HSV-2 positivity was the sole independent predictor of elevated replication of HR-HPV (p < 0.001), vaccine HR-HPV (p < 0.001), and non-vaccine HR-HPV (p < 0.021).

Conclusions: FSWs exhibit a high burden of HR-HPV, shaped by co-infections with HIV and HSV-2. HSV-2 independently drives HR-HPV replication, highlighting its role in HPV persistence and cervical cancer risk. Integrated HSV-2 detection and Gardasil-9^® vaccination should be prioritized in cervical cancer elimination strategies targeting high-risk populations in sub-Saharan Africa.

Keywords: HPV detection and genotyping; HPV viral load; HSV-2; cervical cancer; female sex workers; genital veil-based collector device; human papillomavirus (HPV); multiplex real-time PCR; self-sampling; sub-Saharan Africa.

Figure 1

Distribution of HPV genotypes (in percentage) by HIV serostatus (negative or positive) among the 415 study adult female sex workers living in Kisangani, Democratic Republic of the Congo. (A) Low-risk HPV (LR-HPV), high-risk HPV (HR-HPV), and possibly oncogenic HPV (PO-HPV) genotypes; (B) LR-HPV and HR-HPV genotypes targeted by the 9-valent Gardasil-9^® vaccine; (C) LR-HPV, HR-HPV, and PO-HPV genotypes not targeted by the Gardasil-9^® vaccine. HPV genotypes were determined from veil-based collected genital samples positive for HPV molecular detection using the BMRT HPV Genotyping Real Time PCR assay (Bioperfectus Technologies Co., Ltd., Taizhou, Jiangsu, China). Nota bene. According to the manufacturer’s instructions and in accordance with the HPV classification nomenclature provided by the International Agency for Research on Cancer [50], the BMRT HPV Genotyping Real Time PCR Kit distinguishes 21 HPV genotypes, including 13 HR-HPV genotypes (HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, and -68), three LR-HPV types (HPV-6, -11, and -81) and four genotypes classified as possibly oncogenic (HPV-26, -53, -66, -73, and -82). Nota bene. The 9-valent Gardasil-9^® vaccine (Merck & Co. Inc., NJ, USA) targets the seven HR-HPV genotypes predominantly isolated in cervical cancer (HPV-16, -18, -31, -33, -45, -52, and -58) and two LR-HPVs (HPV-6 and HPV-11).

Figure 2

Distribution of HPV genotypes (in percentage) by genital HSV-2 DNA status (negative or positive) among the 415 study adult female sex workers living in Kisangani, Democratic Republic of the Congo. (A) Low-risk HPV (LR-HPV), high-risk HPV (HR-HPV), and possibly oncogenic HPV (PO-HPV) genotypes; (B) LR-HPV and HR-HPV genotypes targeted by the 9-valent Gardasil-9^® vaccine; (C) LR-HPV, HR-HPV, and PO-HPV genotypes not targeted by the Gardasil-9^® vaccine. HPV genotypes were determined from veil-based collected genital samples positive for HPV molecular detection using the BMRT HPV Genotyping Real Time PCR assay (Bioperfectus Technologies Co., Ltd., Taizhou, Jiangsu, China). Nota bene. According to the manufacturer’s instructions and in accordance with the HPV classification nomenclature provided by the International Agency for Research on Cancer [50], the BMRT HPV Genotyping Real Time PCR Kit distinguishes 21 HPV genotypes, including 13 HR-HPV genotypes (HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, and -68), three LR-HPV types (HPV-6, -11, and -81) and four genotypes classified as possibly oncogenic (HPV-26, -53, -66, -73, and -82). Nota bene. The 9-valent Gardasil-9^® vaccine (Merck & Co. Inc., NJ, USA) targets the seven HR-HPV genotypes predominantly isolated in cervical cancer (HPV-16, -18, -31, -33, -45, -52, and -58) and two LR-HPV (HPV-6 and HPV-11).