Effects of ART initiation on human papillomavirus antibody response

Starting ART may improve antibody responses that in turn reveal exposure to serotypes of human papillomavirus (HPV) that are a high risk for anal cancer.

Jean-Damien Combes from the International Agency for Research on Cancer, Lyon, and colleagues investigated the effects that ART-mediated immune reconstitution has on the appearance of HPV antibodies and their prognostic value for predicting risk of cancer. [1]

High risk HPV serotypes, in particular HPV-16, can cause persistent anal infection and lead to higher rates of anal cancer in HIV positive men. Combes and colleagues assessed antibodies to HPV antigens L1 and E6 that are useful clinical indicators. L1 antibodies do not always develop after HPV infection, but they are an indication of cumulative exposure to HPV. E6 antibodies are highly specific markers of HPV-related cancer and may occur years before cancer diagnosis, though they are more associated with oropharyngeal than anal and cervical cancers.

The researchers conducted this sero-epidemiological study of 281 HIV positive gay men who started ART between 1995 and 2004 in the Swiss HIV Cohort Study to evaluate HPV L1 and E6 antibodies before and after ART. Men who had available serum samples taken within one month before ART and 21 to 27 months after ART initiation were identified for the study. A multiplex HPV serology assay was used to determine the presence of antibodies to the L1 antigen of HPV serotypes 6, 11, 16, 18, 31, 33, 35, 45, 52 and 58, as well as to the E6 antigen of HPV-16. Individuals diagnosed with HPV-related cancer after ART initiation were identified from the cohort database or through linked registries.

Before starting ART, 32.4% of participants had detectable antibodies against HPV-16 L1 antigen. Seropositivity for other high-risk HPV types was as high as 17.8% for HPV-31. Seropositivity for at least one high-risk HPV type was 45.2%. One person was positive for HPV-16 E6 antigen.

After starting ART, seropositivity increased for all HPV antibodies including to 60.5% for at least one high risk type. Prevalence of antibodies to HPV-16 L1 rose to 48%, which corresponds to a prevalence ratio of 1.48 (95%CI: 1.20 to 1.83) compared with before ART. Seropositivity for HPV-31 increased to 34.5%. Two additional individuals seroconverted for HPV-16 E6 antibodies. Seroconversion to HPV-16 L1 after initiation of ART was associated with low CD4 count and low CD4 ratio when starting ART. This result was consistent with L1 seroconversion for any high risk HPV type.

Five cases of anal cancer were diagnosed during 3771 person-years of follow up. Anal cancer only occurred in participants who were positive for antibodies against HPV-16 L1 antigen after initiation of ART. The participant who was HPV-16 E6 antibody positive before ART did not go on to develop any cancer. Of the two participants who seroconverted for HPV-16 E6 antibody after ART, one died seven months later from lymphoma and the other developed anal cancer nine years later. Anal cancer incidence among the three HPV16-E6-positives post-HAART was significantly increased compared with HPV16-E6-negatives (IRR: 63.1, 95%CI: 1.1 to 1211).

In this study, half the participants were seropositive for at least one high risk HPV type before starting ART and a further one-fifth seroconverted to the L1 antigen of high risk HPV types over the following two years. Those with the lowest CD4 counts and lowest CD4:CD8 ratio before starting ART were most likely to seroconvert after ART. The researchers suggest that this indicates that anal exposure to HPV is not sufficient to reveal a detectable antibody response and that ART-mediated immune reconstitution makes an important contribution to the appearance of HPV antibodies. Although cancer cases were small, ART-related seroconversion appeared to improve the ability of HPV-16 L1 and E6 antibody to predict cancer risk.