| |
ART Reduced HPV Prevalence - 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
|
| |
| |
Download the PDF here
February 25, 2020 - Lancet - Helen Kelly, Admire Chikandiwa, Laia Alemany Vilches, Joel M Palefsky, Silvia de Sanjose, Philippe Mayaud
• This study has practical implications for the management of people living with HIV and anal cancer control worldwide. The current recommendations of encouraging earlier ART initiation, coupled with a focus on rapid virological control and sustained adherence, are likely to lead to an earlier and possibly more functionally complete mucosal immune reconstitution, in turn leading to clearance of anal high-risk HPV and control of associated anal lesion development.....The populations comprised 417 006 people living with HIV (women, men who have sex with men, and men who have sex with women). ....ART users with sustained undetectable HIV PVL had 44% lower risk of anal cancer than those without (adjusted HR 0⋅56
To our knowledge, this is the first meta-analysis investigating the association of ART use, HIV plasma viral load, and CD4 cell count with the outcomes of anal high-risk HPV, cytology-confirmed and histology-confirmed anal SIL, and anal cancer incidence in people living with HIV. The results indicate that people living with HIV who receive ART have a decreased prevalence of high-risk HPV, and those with undetectable HIV viral load have decreased risk of high-grade lesion (HSIL-AIN2+) prevalence. Overall, ART was not found to be associated with anal cancer risk, but the subgroup of ART users with sustained undetectable HIV viral load had a 44% reduced risk of anal cancer. Furthermore, an increase in nadir CD4 cell counts of 100 cells per μL was associated with a 40% reduction in anal cancer incidence.
• People living with HIV receiving ART had 35% lower high-risk HPV prevalence than ART-naive people (crude odds ratio [OR] 0⋅65, 95% CI 0⋅54-0⋅79; I2 12⋅1%, p=0⋅31) in 18 studies, and prolonged ART use was associated with a 10% reduction per year in high-risk HPV prevalence in two studies (adjusted OR 0⋅90, 0⋅85-0⋅95; I2 0%, p=0⋅88). People living with HIV with undetectable PVL had lower HSIL-AIN2+ prevalence than those with detectable PVL (crude OR 0⋅84, 0⋅72-0⋅98; I2 0%, p=0⋅80) in 16 studies, particularly if sustained for more than 1 year (crude OR 0⋅62, 0⋅47-0⋅81; I2 0%, p=0⋅51).
Summary
Background
The effect of antiretroviral therapy (ART) on the natural history of anal high-risk HPV and anal lesion progression is not well established. We reviewed the association of ART and other HIV-related factors on anal HPV infection, anal intraepithelial neoplasia (AIN), and anal cancer among people living with HIV.
Methods
For this systematic review and meta-analysis, we searched MEDLINE and EMBASE for studies published between Jan 1, 1996, and Oct 30, 2019, that reported the association of HIV-related exposures (ART or highly active ART [HAART], HIV-RNA plasma viral load [PVL], and nadir or current CD4 cell count) with outcomes of anal high-risk HPV prevalence, incidence, and persistence; prevalence, incidence, progression, or regression of anal histological and cytological abnormalities; and anal cancer incidence. Effect estimates were extracted whenever available; otherwise, they were calculated from raw data. We assessed the risk of bias of included studies using the Newcastle-Ottawa scale, and random-effects meta-analyses were done to examine heterogeneity using the I2 statistic. This study is registered on the PROSPERO database, CRD42018007271.
Findings
We identified 6777 studies, of which 5377 were excluded before full-text review. 122 studies providing estimates for 130 distinct populations matched the inclusion criteria. The populations comprised 417 006 people living with HIV (women, men who have sex with men, and men who have sex with women). 41 (32%) population estimates were not stratified by sex or sexual orientation. People living with HIV receiving ART had 35% lower high-risk HPV prevalence than ART-naive people (crude odds ratio [OR] 0⋅65, 95% CI 0⋅54-0⋅79; I2 12⋅1%, p=0⋅31) in 18 studies, and prolonged ART use was associated with a 10% reduction per year in high-risk HPV prevalence in two studies (adjusted OR 0⋅90, 0⋅85-0⋅95; I2 0%, p=0⋅88). People living with HIV with undetectable PVL had lower HSIL-AIN2+ prevalence than those with detectable PVL (crude OR 0⋅84, 0⋅72-0⋅98; I2 0%, p=0⋅80) in 16 studies, particularly if sustained for more than 1 year (crude OR 0⋅62, 0⋅47-0⋅81; I2 0%, p=0⋅51). ART was not associated with anal cancer incidence when adjusted for years living with HIV in three studies (adjusted hazard ratio [HR] 1⋅11, 95% CI 0⋅68-1⋅80; I2 0%, p=0⋅57), but ART users with sustained undetectable HIV PVL had 44% lower risk of anal cancer than those without (adjusted HR 0⋅56, 0⋅44-0⋅70; I2 0%, p=0⋅94) and for each increase in nadir CD4 cell counts of 100 cells per μL, there was a 40% decrease in anal cancer incidence (crude HR 0⋅60, 0⋅46-0⋅78; I2 21⋅7%, p=0⋅26).
Interpretation
Effective ART use and early initiation at high nadir CD4 counts might reduce anal high-risk HPV infection and anal cancer risk. 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.
There were 25 (19%) separate effect estimates for women (n=5221), 57 (44%) for MSM (n=33 888), and seven (5%) for MSW (including male users of injectable drugs; n=1084). 16 (12%) effect estimates included men only but were not stratified by sexual orientation (n=82 164 men) and 25 (19%) effect estimates included women and men but were not stratified by sex or sexual orientation (n=294 649 people living with HIV). Two studies included both MSM and MSW (or male users of injectable drugs), but presented separate effect estimates for each group, and three studies included women, MSM, and MSW, but presented separate effect estimates for each group
The pooled prevalence of ART use was 77⋅9% (95% CI 72⋅6-83⋅2) in women, 74⋅7% (70⋅4-78⋅9) in MSM, and 79⋅7% (71⋅8-87⋅5) in MSW (appendix p 11), and of undetectable HIV PVL was 71⋅2% (63⋅0-79⋅4), 67⋅0% (60⋅1-73⋅9), and 62⋅5% (47⋅0-77⋅9), respectively. Most studies reported HIV viral detection in all enrolled participants, and not in ART users alone. Of 40 studies with available data for distinct populations of women, MSM, and MSW, 3192 of 5888 of women and 42 of 660 of MSW reported ever practicing receptive anal intercourse, corresponding to a pooled prevalence of 34⋅6% for women and 6⋅8% for MSW (appendix p 11). 4338 of 8099 MSM (pooled prevalence 60⋅4%) reported recent (≤12 months) receptive anal intercourse. In women, the pooled prevalence of anal high-risk HPV was 43⋅8%, 18⋅3% for ASCUS-AIN1+, and 13⋅7% HSIL-AIN2+ (appendix p 11). In MSW, these estimates were 28⋅6%, 23⋅6%, and 4⋅1%; for MSM, they were 69⋅0%, 38⋅0%, and 30⋅5%.
In the meta-analysis of the association of ART and anal high-risk HPV prevalence from 18 studies, people living with HIV and receiving ART had a 35% lower risk of anal high-risk HPV prevalence than ART-naive individuals (crude OR 0⋅65, 95% CI 0⋅54-0⋅79; adjusted OR 0⋅45, 0⋅19-1⋅07, for any nadir or current CD4 count, HIV PVL, or history of receptive anal intercourse), with a low degree of heterogeneity between studies (I2 24⋅7% for adjusted estimate, p value for heterogeneity 0⋅27; table 2, figure 2). In two studies, there was a 10% reduction in high-risk HPV prevalence per additional year of ART (table 2). Compared with detectable HIV PVL, undetectable HIV PVL was associated with a 33% reduction in high-risk HPV prevalence in 17 studies (table 2) and 36% reduction in HPV16 prevalence in four studies (crude OR 0⋅64, 0⋅43-0⋅97; I2 17⋅9%, p=0⋅30; appendix p 24).
In four studies, high nadir CD4 cell counts were associated with lower prevalence of anal high-risk HPV than low nadir CD4 cell counts in women only (≥200 vs <200 cells per μL; crude OR 0⋅62, 0⋅43-0⋅90; I2 0%, p=0⋅74; appendix p 19). Increased current CD4 counts (≥500 vs <500 cells per μL at the time of outcome measurement) were associated with a 28% reduction in high-risk HPV prevalence (table 2) and for each 100 cells per μL increase of current CD4, there was an 11% reduction in high-risk HPV prevalence (table 2) but no association was observed with HPV16 prevalence (appendix p 24).
There was a 16% reduction in HSIL-AIN2+ prevalence in people living with HIV with undetectable HIV PVL (table 2) in 16 studies, especially if sustained over a long period (≥1 year; table 2, figure 4), as shown in four studies.
The prevalence of HSIL-AIN2+ was also decreased in people living with HIV with high nadir CD4 counts (table 2) but not in people with high current CD4 counts.
In nine studies of 141 877 people living with HIV, ART use was associated with a 34% increase in anal cancer incidence compared with no ART use, but this association did not persist when restricted to studies that adjusted for either nadir CD4 cell count, duration of ART use, previous AIDS event, or years living with HIV (adjusted HR 1⋅11, 95% CI 0⋅68-1⋅80; I2 0%, p=0⋅57; table 2, figure 5). Two studies reported a 6% increased risk of anal cancer per year in patients receiving ART, but associations were not significant in the analysis adjusted for pre-ART CD4 count and HIV RNA concentration.
In two studies of 56 190 people living with HIV receiving ART in the USA, individuals with sustained undetectable HIV PVL (defined as percent follow-up time with undetectable HIV PVL ≥80% vs ≤20% of the time and percent follow-up time with undetectable HIV PVL ≥80% vs <40% of the time) had a 44% decreased risk of anal cancer incidence (adjusted HR 0⋅56, 0⋅44-0⋅70; I2 0%, p=0⋅94; table 2, figure 5). A high nadir CD4 cell count of 200 cells per μL or more was associated with 67% decreased risk of anal cancer incidence in three studies of 19 775 people living with HIV.
For each increase of nadir CD4 count of 100 cells per μL, there was a 40% reduction in anal cancer incidence (crude HR 0⋅60, 0⋅46-0⋅78; I2 21⋅7%, p=0⋅26; table 2, figure 5).
|
|
| |
| |
|
|
|
