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HIV-positive women have higher risk of HPV infection, precancerous lesions, and cervical cancer: a systematic review and meta-analysis
 
 
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"we evaluate the risk of HPV incidence, persistence, and progression to cervical lesions and cancer among HIV-positive women compare to HIV-negative women. We additionally assess these relationships by CD4+ cell counts, HIV viral load(VL), and ART use.....
HIV infection was associated with higher incidence of and reduced clearance of HPV infection. Women with low CD4 count and high HIV VL had elevated risk of HPV acquisition, but risk was reduced among ART-adherent women. Low CD4 count was also associated with decreased HPV clearance. While ART reduced LSIL incidence, its impact on HSIL incidence depended on the duration of use. HIV-positive women have lower likelihood of LSIL regression, and ART and high CD4 count were associated with increased LSIL regression. In contrast, HSIL regression was not associated with HIV status. However, the study that examined HSIL regression had a small sample size and should be interpreted with caution. This review identified gaps in the research on HPV and cervical pre-cancer among HIV-positive women. There is a lack of studies investigating impact of ART on HPV disease progression using objective measures of adherence (e.g. viral suppression). Due to influence of HIV-related disease severity, evaluating HPV progression in by nadir CD4 count would be useful. Further, studies comparing HPV progression between HIV-positive women on ART with HIV-negative women can provide insight into CC risk of virally suppressed HIV-positive women. Finally, accurate estimates of CC incidence by HIV status are needed; national cancer registries do not currently document HIV status of CC cases."
 
Liu, Guia; Sharma, Monishab; Tan, Nicholasb; Barnabas, Ruannea,b,c,d AIDS Jan 24 2018
 
Objectives: HIV-positive women have higher human papillomavirus (HPV) prevalence and cervical cancer (CC) incidence than HIV-negative women, partly due to HIV's modifying effect on HPV pathogenesis. We synthesized the literature on the impact of HIV on HPV natural history.
 
Design: Systematic review and meta-analysis
 
Methods: We searched the literature for studies evaluating HPV acquisition and persistence or precancer progression by HIV status. Data on HPV natural history by HIV status, CD4+ cell counts, viral load, and antiretroviral therapy (ART) were summarized using fixed effect models.
 
Results: Overall, 38 of 1845 abstracts identified met inclusion criteria. HIV-positive women had higher HPV acquisition (relative risk [RRpooled]=2.64, 95% confidence interval [CI] 2.04-3.42) and lower HPV clearance (hazard ratio [HRpooled]=0.72, 95% CI 0.62-0.84) than HIV-negative women. HPV acquisition was higher with declining CD4 and was lower in those virally suppressed on ART. HIV was associated with higher incidence of low-grade squamous intraepithelial lesions (LSIL) (RRpooled=3.73, 95% CI 2.62-5.32) and high-grade squamous intraepithelial lesions (HSIL) (HRpooled=1.32, 95% CI 1.10-1.58), largely due to increased HPV persistence. ART lowered progression from normal cytology to LSIL (HRpooled=0.65, 95% CI 0.52-0.82), but not HSIL. CC incidence was associated with HIV positivity (RR=4.1, 95% CI 2.3-6.6), but not with ART.
 
Conclusions: HIV-positive women have higher risk of acquiring HPV, with risk inversely associated with CD4 count. ART lowered HPV acquisition, increased clearance, and reduced precancer progression, likely via immune reconstitution. While some of our results are limited by small number of studies, our study can inform screening guidelines and mathematical modeling for CC prevention.
 
Introduction
 
Cervical cancer (CC) is the fourth most common cancer in women worldwide and the most common cancer among women in sub-Saharan Africa [1].Sub-Saharan Africa has high dual burden of human papillomavirus (HPV) and HIV infection [2,3]. HIV is associated with higher rates of HPV acquisition, decreased clearance of HPV and precancerous lesions, and increased risk of CC[4,5]. Compared to HIV-negative women, CC mortality in HIV-positive women is ∼2- times higher[6,7]. With increasing life expectancy of HIV-positive women on antiretroviral treatment (ART), there is a growing need for CC prevention,particularly in low resources settings [8].In the United States, CC screening programs have been highly effective in reducing CC incidence and HPV vaccines have been shown to reduce the prevalence of HPV 16 and 18-attributable precancer lesions [9,10].However, availability of HPV vaccines and CC screening is extremely limited in developing settings, although efforts to scale up screening are ongoing in Zambia[11,12]. CC screening coverage in the last 3 years among eligible women is less than 6% in Kenya and 23% in South Africa [13].
 
CC screening is not without harm and research on the optimal screening interval for HIV-positive women is still emerging [14]. In September 2015, the recommended CC screening interval for HIV-positive women with normal cytology was changed from annually to every 3 years in the United States [15]. A better understanding of the impact of HIV on HPV natural history can help inform CC screening and prevention policies for HIV-positive women.
 
Further, although many studies have evaluated the relationship between HIV and HPV pathogenesisthe findings have not been synthesized. While ART decreases the incidence of other AIDS-related cancers, its relationship with CC is unclear [16,17,14]. We conducted a systematic review and meta-analysis to synthesize the literature on HPV natural history in HIV-positive women. Specifically, we evaluate the risk of HPV incidence, persistence, and progression to cervical lesions and cancer among HIV-positive women compare to HIV-negative women. We additionally assess these relationships by CD4+ cell counts, HIV viral load(VL), and ART use.
 
Discussion
 
HIV infection was associated with higher incidence of and reduced clearance of HPV infection. Women with low CD4 count and high HIV VL had elevated risk of HPV acquisition, but risk was reduced among ART-adherent women.
Low CD4 count was also associated with decreased HPV clearance. While ART reduced LSIL incidence, its impact on HSIL incidence depended on the duration of use. HIV-positive women have lower likelihood of LSIL regression, and ART and high CD4 count were associated with increased LSIL regression. In contrast, HSIL regression was not associated with HIV status. However, the study that examined HSIL regression had a small sample size and should be interpreted with caution.
 
While the relative risk of acquiring HPV 16/18 was higher among HIV-positive women, HPV 16/18 clearance was not foundto differ by HIV status. This may be due to a lack of power or it may be that HPV 16 and 18 are better at evading the host immune system and are less impacted by HIV-associated immunosuppression [56,57]. Studies have found that HPV 16 in particular is more weakly associated with the immune system compared to other types [58,59]. This is consistent with studies that find HIV-positive women have a greater diversity of HPV types in normal cytology and low-grade lesions, but the relative prevalence of HPV 16 and 18 increases with severity of lesions and CC and the proportion of CC attributable to HPV 16/18 is similar between HIV positive and negative women [57,60].
 
HIV was also associated with higher LSIL and HSIL incidence, although the relative impact on HSIL was smaller. This suggests that immunosuppression related to HIV infection may play a greater role earlier in the course of HPV natural history, namely acquisition, persistence, and progression to low-grade lesions, while later stage carcinogenicity may be less dependent on immune function. This is consistent with cohort studies that find that, although HIV-positive women have a high burden of abnormal cytology, the vast majority of lesions are low-grade, with only a small increased prevalence in HSIL [45,61]. Therefore, HIV-positive women may be at risk for overtreatment in screening programs as they have a high prevalence of low-grade lesions that infrequently progress to HSIL. The US has recently changed CC screening guidelines in HIV-positive women from annual screening to every 3 years after 3 consecutive normalscreens [15].
 
CD4 cell count in HIV-positive women is inversely associated with risk of HPV infection and cervical lesion progression. Further, several studies showed that women with high CD4 count (>500 cells/mm3) had similar risk of HPV disease progression as HIV-negative women. Similar associations between immunosuppression and HPV risk have been observed in HIV-negative populations with impaired immune system [62-65]. A meta-analysis of cancer incidence in HIV-positive persons and transplant recipients found both groups were at higher risk of cancers with infectious etiology compared to the general population [65].
 
The destruction of CD4 cells by HIV may increase the likelihood of HPV establishing infection [66]. Recent evidence also suggests that immunosuppression leads to higher probability of HPV reactivation, potentially due to incomplete clearance of HPV DNA [67].
 
HPV persistence likely plays an important role in the interactions between HIV and HPV. HIV-positive women with persistent HPV infection have dramatically higher incidence of precancerous lesions compared to those infected with HPV for <6 months [36,39,46]. Studies find after controlling for HPV persistence, CD4 count and ART use are no longer associated with increased risk of HPV disease progression. This is likely because HIV acts through HPV persistence to increase risk of precancerous lesions. Women infected with HPV for longer have a greater chance of developing cellular changes that lead to precancer or cancer.
 
The effect of ART on HPV-related disease is less clear. An equal number of studies find ART is associated with reduced HPV disease progression and find no association between ART and HPV pathogenesis. The equivocal results may be due to changes in ART regimens over time or varying durations of ART use. The majority of studies showing no effect of ART used cohorts formed in the early days of ART. Due to high toxicity of the older ART drugs, healthier HIV-infected individuals likely delayed treatment initiation and had poor adherence. Therefore, the women who were on ART likely already had more advanced HIV disease at treatment initiation.
 
Studies show that HIV disease state at ART initiation significantly impacts morbidity and mortality [68-70]. Further, many studies finding no association approximated ART use with medical records or self-report. Studies using more accurate measures of ART adherence (e.g. viral suppression), found ART reduces HPV disease progression. One study found significantly lower incidence of HPV infection and cervical lesions in women who were virologically suppressed on ART compared to women who not on ART or not virologically suppressed [27].
 
A study showed CC cases had higher odds of CD4 decline on ART prior to CC diagnosis compared to controls who did not subsequently develop CC, which may indicate a disruption in ART use prior to the development of CC [71]. A longer duration on ART is also associated with reduced HSIL incidence [4,47], which may indicate immune system recovery [72]. In addition to the limitations of including studies that ascertained ART status through self-reports and chart reviews, another potential limitation of this review is the heterogeneity of studies included. While majority of studies were longitudinal, variation in analysis, effect measures, and exposures definition limited our ability to perform quantitative analysis. Additionally, due to small number of studies eligible for some objectives, we could not use I2 to quantifyheterogeneity in many cases. High loss to follow up was an issue for some of the studies we included. While this limitation was ameliorated with survival analysis methods that censored individuals lost to follow up, effect estimates may be biased in studies that did not address this limitation in their analysis. The magnitude and direction of bias would depend on whether the lost to follow up was differential by HIV, ART, CD4 or VL status.
 
This review identified gaps in the research on HPV and cervical pre-cancer among HIV-positive women. There is a lack of studies investigating impact of ART on HPV disease progression using objective measures of adherence (e.g. viral suppression). Due to influence of HIV-related disease severity, evaluating HPV progression in by nadir CD4 count would be useful. Further, studies comparing HPV progression between HIV-positive women on ART with HIV-negative women can provide insight into CC risk of virally suppressed HIV-positive women. Finally, accurate estimates of CC incidence by HIV status are needed; national cancer registries do not currently document HIV status of CC cases.

 
 
 
 
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