HIV

Helen Kelly, PhD, on the Impact of ART Use on Anal HR-HPV Infection and Anal Cancer Risk

A new systematic review and meta-analysis, published in The Lancet HIV, indicated that effective use of antiretroviral therapy (ART) and early initiation of ART at high nadir cluster of differentiation 4 (CD4) counts may be associated with decreased anal high-risk human papillomavirus (HR-HPV) infection and risk of anal cancer among people with HIV.

“Although most studies were cross-sectional in design and few adjusted for potential confounders, this analysis provides comprehensive estimates of the effect of ART and HIV-related factors on the natural history of anal HPV-related disease in people living with HIV,” the authors of the study wrote.

Using MEDLINE and EMBASE, the researchers assessed data from 122 studies (N = 417,006 people living with HIV, including men who have sex with men, men who have sex with women, and women) published between Jan 1, 1996, and Oct 30, 2019. All studies included in the present analysis met the following inclusion criteria:

  • Assessed the relationship between HIV-related exposures (ART or highly active ART, nadir or current CD4 cell count, and HIV-RNA plasma viral load [PVL]) and outcomes of anal high-risk HPV incidence, prevalence, and persistence
  • Examined the incidence, prevalence, progression, or regression of anal histological and cytological abnormalities
  • Evaluated the incidence of anal cancer


The researchers noted that 41 (32%) population estimates were not categorized based on sex or sexual orientation. Ultimately, the results of the systematic review and meta-analysis were:

  • In 18 studies, ART-treated people living with HIV had a 35% lower prevalence of HR-HPV compared with ART-naive people (crude odds ratio [OR] 0.65).
  • In 2 studies, prolonged use of ART was associated with a 10% yearly decrease in the prevalence of HR-HPV (adjusted OR 0.90).
  • In 16 studies, HSIL-AIN2+ prevalence was lower among people living with HIV with undetectable PVL compared with those with detectable PVL (crude OR 0.84), especially if undetectable PVL was sustained for more than 1 year (crude OR 0.62).
  • In 3 studies, after adjustment for years living with HIV, ART was not associated with anal cancer incidence (adjusted hazard ratio [HR] 1.11). However, ART-treated people with sustained undetectable HIV PVL had a 44% lower risk of anal cancer compared with those who were not treated with ART (adjusted HR 0.56). Each increase in nadir CD4 cell counts of 100 cells per μL was associated with a 40% reduction in the incidence of anal cancer (crude HR 0.60).


Infectious Diseases Consultant discussed the implications of these findings further with corresponding study author Helen Kelly, PhD.

ID CON: What prompted you and your colleagues to study the effect of ART on the natural history of anal high-risk HPV and anal lesion progression?

Dr Kelly: For many people living with HIV today with access to combination ART, it is possible to live a long and healthy life when regularly taking combination ART. However, people living with HIV remain at increased risk of comorbidities including HPV-associated cancers, such as anal cancer compared, with the general population. Control and prevention measures for anal cancer are limited in terms of access to and accuracy of screening for these cancers, as well as access to HPV vaccination among people living with HIV.

In a previous analysis, we reported that women living with HIV taking ART had a decreased risk of cervical high-risk HPV infection and decreased incidence of invasive cervical cancer compared to ART-naïve women. We felt that a similar review of the evidence of the impact of ART on anal HR-HPV, anal lesion, and anal cancer incidence among women and men living with HIV was needed.

ID CON: You and your colleagues found that “effective ART use and early initiation at high nadir CD4 counts might reduce anal high-risk HPV infection and anal cancer risk.” Could you elaborate on the significance of this finding?

Dr Kelly: Previous studies have demonstrated the clinical benefit of early ART initiation, including the reduction of infection-related cancers, as well as many other comorbidities affecting people living with HIV. Current guidelines now indicate starting ART for all people living with HIV irrespective of CD4+ count, and many countries around the world are moving towards immediate ART in alignment with the UNAIDS 90-90-90 goals. If people living with HIV are able to access ART early and use it consistently, this may lead to a reduction in anal cancer incidence among women and men living with HIV in the future.

On the other hand, there will be settings where immediate and unconditional ART may not be readily available, and people living with HIV may initiate ART at lower CD4 counts. In this context, ensuring a high level of adherence to achieve sustained HIV viral suppression over prolonged duration, ART may help to reduce the risk of anal lesion development and ultimately anal and cervical cancer incidence.

The role of ART in the control of anal lesion development and anal cancer incidence is especially important given the current limitations in, and low access to, screening for anal cancer among people living with HIV.

ID CON: What key clinical takeaways would you like to leave with infectious disease specialists on this topic?

Dr Kelly: We found in this review that there was a high prevalence of anal HR-HPV, accompanied with high prevalence of high-grade anal lesions among people living with HIV, being highest among men who have sex with men, followed by women, and men who have sex with women.

We found in the review that people living with HIV taking ART had up to a 35% decreased risk of anal HR-HPV infection compared with those not on ART, and each additional year on ART was associated with a 10% reduction in anal HR-HPV infection.

People living with HIV with undetectable HIV plasma viral load that was sustained over time had a 44% lower risk of anal cancer compared with those with detectable HIV plasma viral load. Further, people living with HIV who started ART early had a decreased risk of anal cancer; for each 100 cells per µl increase in nadir CD4+ cell count, there was a 40% reduction in anal cancer incidence. These findings suggest that current rather than historical immunosuppression may be effective at clearing HR-HPV infection, while measures of past immunosuppression may be more predictive of anal cancer risk.

Given the high prevalence of anal HR-HPV and associated lesions among people living with HIV and the challenges in diagnosis and effective management of anal lesions, this review points to yet one more reason to emphasize early diagnosis of HIV infection and immediate initiation of effective ART among populations at increased risk of anal cancer.

ID CON: What are the next steps for future research in this area?

Dr Kelly: Despite the large number of studies included in this review, few evaluated the impact of ART prospectively on anal lesion progression, regression, or recurrence. Prospective cohort studies should aim to determine whether patients with early ART initiation do indeed experience a reduced incidence of anal cancer compared with the general population. This monitoring of anal cancer incidence among people living with HIV globally in the era of universal and early ART should help in understanding who is at highest risk and who may need screening.

Given the limitations of current screening modalities for anal cancer, better biomarkers are needed for early detection of those needing treatment.

HPV vaccination of people living with HIV may be of great benefit and help reduce incidence of disease. Its impact and cost-effectiveness should be evaluated through modeling or demonstration studies.

—Christina Vogt

Reference:
Kelly H, Chikandiwa A, Alemany Vilches L, Palefsky JM, de Sanjose S, Mayaud P. Association of antiretroviral therapy with anal high-risk human papillomavirus, anal intraepithelial neoplasia, and anal cancer in people living with HIV: a systematic review and meta-analysis [Published online February 25, 2020]. Lancet HIV. doi:10.1016/S2352-3018(19)30434-5