Impact of Hormonal Contraceptives on HPV Dynamics in Adolescent Girls and Young Women: Insights from a Randomized Controlled Sub-Study in South Africa

Abstract

Objectives: Human papillomavirus (HPV) is the leading cause of cervical cancer, with adolescent girls and young women (AGYW) in sub-Saharan Africa carrying a disproportionately high burden of infection. Hormonal contraceptives may influence HPV acquisition, persistence, and clearance, but evidence remains inconclusive. This sub-study aimed to evaluate the impact of different hormonal contraceptives on HPV prevalence and genotype distribution in AGYW.

Methods: Ninety-eight HIV-seronegative AGYW aged 15-19 years from South Africa were randomized to receive one of three hormonal contraceptive methods: norethisterone enanthate (Net-EN) injectable, combined oral contraceptive pills (COCPs), or the etonorgesterol/ethinyl estradiol combined contraceptive vaginal ring (CCVR). Cervical DNA samples were collected at baseline and after 16 weeks for HPV genotyping using the HPV Direct Flow Chip test. HPV prevalence, persistence, clearance, and acquisition were analyzed across contraceptive methods.

Results: At baseline, HPV prevalence was high (94.9%), with no differences among contraceptive arms. After 16 weeks, HPV prevalence remained high (89.5%) across groups. No significant differences were observed in overall HPV prevalence or genotype distribution by contraceptive method. Longitudinal analysis revealed that AGYW using Net-EN tended to have a higher cumulative number of high-risk HPV (HR-HPV) genotypes that cleared whereas those using CCVR acquired more HR-HPV types and had greater HR-HPV persistence compared to other groups.

Conclusions: This study highlights the high burden of HPV among South African AGYW. However, different hormonal contraceptive methods did not significantly influence HR-HPV dynamics.

Keywords: CCVR; COCPs; HPV; Human papillomavirus; Net-EN; adolescents; contraceptives; persistence.

Figure 1.. Dynamics of HPV Infections Across Contraceptive Methods.

This figure illustrates the percentage of AGYW with cleared, persistent, and newly acquired HPV infections, based on paired data between baseline and week 16 visits. Results are stratified by hormonal contraceptive methods: CCVR (n=26), COCPs (n=25), and Net-EN (n=36). Color coding reflects infection categories: pink for any HPV, orange for HR HPV, darker blue for LR-HPV, and lighter blue for multiple HPVs.

Figure 2.. HPV Genotype Distribution Across Contraceptive Arms.

(A) Distribution of HPV genotypes among AGYW at baseline and 16 weeks. Each bar graph represents the prevalence of a specific HPV genotype. Light colors indicate low-risk HPV (LR-HPV) types, while dark colors represent HR-HPV types. Genotypes no longer considered by IARC (3) to be HR are shown in green italics. Genotypes targeted by the bivalent (HPV 16, 18), quadrivalent (HPV 6, 11, 16, 18), and nonavalent (HPV 6, 11, 16, 18, 31, 33, 45, 52, 58) vaccines are highlighted in bold. (B) Stacked bars show the prevalence of HR HPV types (including HPV-66 and −68 which were previously classified as HR) that were newly acquired between 0 and 16 weeks (left panel), cleared (middle panel), or persisted (right panel), stratified by genotype and contraceptive method. Panels represent data for Net-EN (n=36), COCPs (n=25), and CCVR (n=26), based on paired samples between baseline and week 16 visits.

Figure 2.. HPV Genotype Distribution Across Contraceptive Arms.

(A) Distribution of HPV genotypes among AGYW at baseline and 16 weeks. Each bar graph represents the prevalence of a specific HPV genotype. Light colors indicate low-risk HPV (LR-HPV) types, while dark colors represent HR-HPV types. Genotypes no longer considered by IARC (3) to be HR are shown in green italics. Genotypes targeted by the bivalent (HPV 16, 18), quadrivalent (HPV 6, 11, 16, 18), and nonavalent (HPV 6, 11, 16, 18, 31, 33, 45, 52, 58) vaccines are highlighted in bold. (B) Stacked bars show the prevalence of HR HPV types (including HPV-66 and −68 which were previously classified as HR) that were newly acquired between 0 and 16 weeks (left panel), cleared (middle panel), or persisted (right panel), stratified by genotype and contraceptive method. Panels represent data for Net-EN (n=36), COCPs (n=25), and CCVR (n=26), based on paired samples between baseline and week 16 visits.