Women infected with HIV may have a lower risk of testing positive for cervical human papillomavirus (HPV) if they have been taking combination antiretroviral therapy (cART) for a longer period of time, according to a prospective cohort study conducted in South Africa.1 Relative to peers who were not receiving this therapy, study participants who were receiving cART had a reduction of two-thirds in the unadjusted odds of HPV types associated with a high risk of cervical cancer and a reduction of one-half in the unadjusted odds of HPV 16, one of the main cancer-causing types. Although these associations were no longer statistically significant after adjustment for covariates, duration of therapy remained an important indicator of risk: With each additional month that a woman used cART, the adjusted likelihood of testing positive fell by 5% and 6%, respectively, for high-risk types and for HPV 16.
Between November 2009 and October 2011, investigators enrolled in the study nonpregnant, cancer-free South African women who were infected with HIV and had never taken cART. During twice-yearly follow-up visits, the women provided clinical, obstetric and sexual behavior data; underwent a Pap test; and gave blood samples for assessment of CD4 cell count and HIV viral load, and cervical samples for HIV and HPV DNA testing. The investigators used bivariate analyses to compare baseline characteristics between women who did and did not initiate cART, and modeled the probability of detection of HPV using multivariate logistic regression analysis as a function of whether women were on cART at a given visit and of the length of time they had been on this therapy.
The 300 women studied were 35 years old, on average. Overall, 68% initiated cART after meeting the criteria in government guidelines; all were started on a regimen containing a non-nucleoside analogue reverse transcriptase inhibitor, standard practice at the time. About 46% of women who initiated cART and 65% of those who did not were black, and the majority (69% and 80%, respectively) had a partner. Mean duration of follow-up was 19 months among those who initiated cART and 12 months among those who did not. On average, the women who started cART stayed on this therapy for 16 months.
Results showed that 94% of women tested positive for at least one high-risk type of HPV (type 16, 18, 31, 33, 35, 39, 45, 52 or 58) at some time during follow-up, and 42% specifically tested positive for HPV 16. In unadjusted analyses, relative to peers who were not using cART, women who were had a roughly 80% reduction in the odds of testing positive for any type of HPV (odds ratio, 0.2), a 70% reduction in the odds of testing positive for any high-risk HPV (0.3) and a 50% reduction in the odds of testing positive for HPV 16 (0.5). Risk fell by 7–9% with each additional month on this therapy.
After adjustment for other factors potentially associated with or affecting HPV acquisition or detection, the associations of cART use with HPV positivity were no longer statistically significant. But risk was still inversely associated with the duration of cART: With each additional month on this therapy, the adjusted odds fell by 4% for any HPV, 5% for high-risk HPV and 6% for HPV 16 (odds ratios, 0.94–0.96 per month).
In other adjusted findings, sexually active women were more likely than other women to test positive for any type of HPV (odds ratio, 1.8) and for HPV 16 specifically (1.8), and the odds of testing positive for any HPV was positively associated with the level of HIV DNA found in cervical cells (1.3). The risk of HPV 16 fell with each month elapsed since excisional treatment of cervical neoplasia (0.96).
Further analysis showed that the reduction in odds seen among women taking cART was smaller for all low-risk types of HPV combined than for HPV 16 (ratio of odds ratios, 1.4). In contrast, the reduction in odds for all high-risk types of HPV combined was statistically indistinguishable from that for HPV 16.
Study strengths included the use of a clearly defined outcome, adjustment for a wide range of variables and assessment of associations with different types and groups of HPV, according to the investigators; limitations included the possible influence of unmeasured confounders and inability to conclude that cervical HIV and HPV are causally related. They speculate that the conflicting results of previous studies of the association of cART with HPV detection may have been due in part to a differential risk reduction seen with this therapy across viral types. Taken together, the study’s findings suggest that cART protects against HPV infection “in a time-dependent and immunology-driven manner,” according to the investigators. “Reducing cervical HPV co-infection in women living with HIV infection should be seen as one of the many benefits of initiating the combination anti-HIV medication,” they conclude.—S. London
1. Zeier MD et al., Combination antiretroviral therapy reduces the detection risk of cervical human papilloma virus infection in women living with HIV, AIDS, 2015, 29(1):59–66.