Copper IUD ups cervicovaginal inflammation, but does not affect HIV risk

While the use of a copper intrauterine device (Cu-IUD) broadly raises levels of cervicovaginal secretion (CVS) cytokines 6 months after insertion, it has no apparent impact on the risk of contracting HIV, according to a new study.

“Our findings from this mucosal mechanism substudy within the first large, randomized, and longitudinal trial of contraceptive methods … demonstrates that the Cu-IUD is significantly more inflammatory than hormonal contraceptives,” despite being offered as a nonhormonal alternative, the researchers said.

This substudy of the randomized ECHO Trial included 149 women from South Africa and Kenya, in whom 27 CVS cytokines were measured at baseline, 1 month, and 6 months after contraceptive initiation. Contraceptives assessed included Cu-IUD (n=52), intramuscular depot medroxyprogesterone acetate (DMPA-IM; n=47), and levonorgestrel implant (LNG-implant; n=50).

At baseline and after 1 month, CVS cytokine profiles were statistically comparable across the three contraceptive groups. But by 6 months, women who had Cu-IUD implants saw significant elevations in 25 of 27 assessed cytokines compared to matched baseline samples. This effect remained significant even after adjusting for multiple comparisons. No such dysregulation was reported in the LNG-implant or DMPA-IM groups. [Int J Infect Dis 2022;doi:10.1093/infdis/jiac084]

Of note, all four inflammatory cytokines (interleukin [IL]-1β, IL-6, IL-12p70, and tumour necrosis factor [TNF]-α) and all seven chemokines (IL-8, eotaxin, interferon-gamma-induced protein 10, monocyte chemoattractant protein [MCP]-1, macrophage inflammatory protein [MIP]-1α, MIP-1β, and RANTES) were all significantly overexpressed in Cu-IUD users. The same was true for most of growth factors, regulatory cytokines, and adaptive cytokines.

Among the elevated CVS cytokines, MIP-1α (median 21.4-fold increase; p=0.0002), MIP-1β (median 7.9-fold increase; p=0.0003), IL-6 (median 10.1-fold increase; p=0.0003), MCP-1 (median 8.6-fold increase; p=0.002), and IL-1β (median 8.4-fold increase; p=0.0002) were most strongly and significantly upregulated.

IL-10 was only moderately elevated in the Cu-IUD group (median 1.4-fold increase; p=0.001), but such effect was coupled by a significant suppression of IL-1RA (median 0.8-fold decrease; p=0.02), indicating an overall dysregulation of the cervicovaginal inflammatory environment.

In a subsequent analysis, the researchers used logistic regression analysis to compare preseroconversion levels of CVS cytokines in participants with (n=25) and without (n=100) HIV.

In the intention-to-treat analysis, unadjusted modelling showed that preseroconversion concentrations of IL-1β, IL-6, TNF-α, eotaxin, IL-2, IL-5, IL-4, and IL-17 were all significantly and positively correlated with the likelihood of contracting HIV. However, multivariable adjustment attenuated the statistical effect of these cytokines.

“We conclude that genital inflammation caused by insertion of the Cu-IUD was not sufficient to increase HIV risk compared to DMPA-IM and LNG-implant in the ECHO Trial,” the researchers said.

“While Cu-IUD-induced genital inflammation did not appear to significantly impact HIV risk in this substudy, these effects may indicate the potential for susceptibility to other pathogens that warrant further investigation,” they added.