Evidence of synergistic relationships between HIV and Human Papillomavirus (HPV): systematic reviews and meta-analyses of longitudinal studies of HPV acquisition and clearance by HIV status, and of HIV acquisition by HPV status

Abstract

Introduction: Observational studies suggest HIV and human papillomavirus (HPV) infections may have multiple interactions. We reviewed the strength of the evidence for the influence of HIV on HPV acquisition and clearance, and the influence of HPV on HIV acquisition.

Methods: We performed meta-analytic systematic reviews of longitudinal studies of HPV incidence and clearance rate by HIV status (review 1) and of HIV incidence by HPV status (review 2). We pooled relative risk (RR) estimates across studies using random-effect models. I² statistics and subgroup analyses were used to quantify heterogeneity across estimates and explore the influence of participant and study characteristics including study quality. Publication bias was examined quantitatively with funnel plots and subgroup analysis, as well as qualitatively.

Results and discussion: In review 1, 37 publications (25 independent studies) were included in the meta-analysis. HPV incidence (pooled RR = 1.55, 95% CI: 1.29 to 1.88; heterosexual males: pooled RR = 1.95, 95% CI: 1.62, 2.34; females: pooled RR = 1.63, 95% CI: 1.26 to 2.11; men who have sex with men: pooled RR = 1.36, 95% CI: 1.01 to 1.82) and high-risk HPV incidence (pooled RR = 2.20, 95% CI: 1.90 to 2.54) was approximately doubled among people living with HIV (PLHIV) whereas HPV clearance rate (pooled RR = 0.53, 95% CI: 0.42 to 0.67) was approximately halved. In review 2, 14 publications (11 independent studies) were included in the meta-analysis. HIV incidence was almost doubled (pooled RR = 1.91, 95% CI 1.38 to 2.65) in the presence of prevalent HPV infection. There was more evidence of publication bias in review 2, and somewhat greater risk of confounding in studies included in review 1. There was some evidence that adjustment for key confounders strengthened the associations for review 2. Misclassification bias by HIV/HPV exposure status could also have biased estimates toward the null.

Conclusions: These results provide evidence for synergistic HIV and HPV interactions of clinical and public health relevance. HPV vaccination may directly benefit PLHIV, and help control both HPV and HIV at the population level in high prevalence settings. Our estimates of association are useful for mathematical modelling. Although observational studies can never perfectly control for residual confounding, the evidence presented here lends further support for the presence of biological interactions between HIV and HPV that have a strong plausibility.

Keywords: HIV; HPV; epidemiology; humans; incidence; meta-analysis; sexually transmitted infections; systematic review.

Figure 1

Results and selection of publications from the literature search.

Figure 2

Forest plots for the crude and adjusted relative risk (RR) of: (a) incident HPV infection; (b) incident HR‐HPV infection; (c) incident HPV‐16/HPV‐18 infection; and (d) incident HPV‐31/HPV‐33/HPV‐45/HPV‐52/HPV‐58 infection, by HIV status. In this plot all HIV infection is prevalent, and the comparison group (unexposed group) is those HIV‐negative. An effect estimate greater than 1 indicates increased HPV incidence in those with HIV infection compared to HIV‐negative individuals. An asterisk next to the effect estimate indicates that this estimate was calculated using data presented in the publication. NA, North America; EU, Europe; SSA, Sub‐Saharan Africa; SA, South America; APAC, Asia and Pacific.

Figure 3

Forest plots for the crude and adjusted relative risk (RR) of: (a) clearance of HPV; (b) clearance of HR‐HPV; (c) clearance of HPV‐16/HPV‐18; and (d) clearance of HPV‐31/HPV‐33/HPV‐45/HPV‐52/HPV‐58, by HIV status. In this plot all HIV infection is prevalent, and the comparison group (unexposed group) is those HIV‐negative. An effect estimate <1 indicates decreased rate of HPV clearance in those with HIV infection compared to HIV‐negative individuals. An asterisk next to the effect estimate indicates that this estimate was calculated using data presented in the publication. NA, North America; EU, Europe; SA, South America; SSA, Sub‐Saharan Africa; APAC, Asia and Pacific.

Figure 4

Forest plot for the crude and adjusted relative risk (RR) of HPV incidence and clearance among PLHIV by CD4 count level compared to HIV‐negative for: (a) incident HPV infection; (b) incident HR‐HPV infection; (c) clearance of HPV; (d) clearance of HR‐HPV. In this plot all HIV infection is prevalent, and the comparison group (unexposed group) is those HIV‐negative. An effect estimate greater than 1 (incident HPV) indicates increased HPV incidence in those with HIV infection compared to HIV‐negative individuals. An effect estimate less than 1 (HPV clearance) indicates decreased rate of HPV clearance in those with HIV infection compared to HIV‐negative individuals. An asterisk next to the effect estimate indicates that the estimate was derived from available information in the publication. For Watts (2005) the estimate refers to clearance of incident HPV types. NA, North America; EU, Europe; SSA, Sub‐Saharan Africa.

Figure 5

Forest plots of the crude and adjusted relative risk (RR) of HIV acquisition for: (a) prevalent HPV infection; (b) incident HPV infection; (c) prevalent HR‐HPV infection; (d) prevalent LR‐HPV infection; (e) HPV‐16/HPV‐18/HPV‐31/HPV‐33/HPV‐52/HPV‐58 infection; (f) clearance of HPV. In this plot HPV infection is the exposure and HIV acquisition is the outcome. An asterisk next to the effect estimate indicates that this estimate was calculated using data presented in the publication. SSA, Sub‐Saharan Africa.