From the Division of Infectious Disease, Department of Medicine, University of California, San Francisco, CA
Conflicts of interest and sources of funding: Merck and Co. has provided travel support to Dr. Palefsky. UCSF has received support from Merck for Dr. Palefsky's activities as a member of a Scientific Advisory Board, educational activities and research grant funding.
Correspondence: Joel Palefsky, MD, CM, FRCP(C), Professor of Medicine, Division of Infectious Diseases, Box 0654, 513 Parnassus Ave., Room S420, University of California, San Francisco, San Francisco, CA 94143. E-mail: email@example.com.
Received for publication April 15, 2012, and accepted May 14, 2012.
A growing body of literature has shown that human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) are at high risk of having anal human papillomavirus (HPV) infection, anal intraepithelial neoplasia (AIN), and anal cancer. Antiretroviral therapy (ART) has profoundly impacted on the survival of HIV-infected individuals and has substantially reduced the incidence of cancers associated with infectious agents, including human herpesvirus-8-associated Kaposi sarcoma and Epstein-Barr virus-associated non-Hodgkin lymphoma.1 However, the effect of ART on HPV infection and HPV-associated disease is far from clear. Van der Snoek et al. add to our body of knowledge on the association between use of ART, anal HPV infection, and AIN in their article describing their Dutch cohort of HIV-positive MSM. They performed a cross-sectional study of 250 HIV-positive MSM that included assessment of anal HPV infection, anal disease using high resolution anoscopy (HRA) and biopsy, and potential risk factors such as use of ART. Their data show that use of ART is associated with reduced prevalence of AIN and anal HPV infection, and they suggest that earlier introduction of ART in treatment-naïve individuals may be considered to reduce the burden of HPV-associated disease in this population.
Relative to the general population, the incidence of anal cancer is increased among MSM, women with a history of cervical and vulvar cancer or high-grade vulvar intraepithelial neoplasia and those with immunosuppression associated with HIV infection or organ transplant.2 Before the advent of ART, the risk of anal cancer among HIV-infected MSM was nearly 60-fold higher than the general population of men.3 However, the effect of ART on HPV-associated squamous cell cancer remains unclear. Anal cancer, in particular, offers the most insight into the effect of ART on HPV-associated cancer. This is because routine screening for anal cancer and the likely anal cancer precursor, high-grade anal intraepithelial neoplasia (HGAIN) is not yet commonplace, and few patients at risk for anal cancer are being screened or treated for HGAIN. In contrast, routine screening for and treatment of high-grade cervical intraepithelial neoplasia are practiced for many (but sadly not all) HIV-infected women on ART, rendering it difficult to determine the full effect of ART on the incidence of cervical cancer.
One piece of data remains indisputable at this point—the incidence of anal and cervical cancer has not declined since the widespread introduction of ART in 1996. Multiple analyses have actually shown the opposite, particularly for anal cancer, which has seen a substantial increase in incidence since ART was introduced.2,4,5 Some studies in the ART era describe rates of anal cancer in HIV-positive men MSM that exceed some of the highest rates of cervical cancer in the world.2,6–8 Historically, anal cancer is a disease of men and women aged >50 years,9,10 and it is likely that progression from HGAIN to cancer may occur over many years or even decades. The leading hypothesis is that those on ART are living longer, and in the absence of routine screening for HGAIN, there is more time for these lesions to progress to cancer.
An understanding of the relationship between ART use, HGAIN, and anal HPV infection may offer some insight into future trends for anal cancer in HIV-positive men and women, and inform development and implementation of anal cancer prevention strategies. If ART has little effect on HGAIN prevalence and incidence, it is possible that the incidence of anal cancer will continue to rise in the absence of prevention efforts. Conversely, if ART is inducing regression of prevalent HGAIN or reducing its incidence, the future might bring a reduction of anal cancer, to least to the levels seen in HIV-negative populations. Unfortunately, the increased incidence of anal cancer in HIV-positive MSM in the ART era suggests that the former scenario may be more accurate. The reasons for the limited impact of ART are not currently understood. These may reflect only partial restoration of ART-associated immune response to HPV antigens, or a limited role of this immune response in clearing HGAIN lesions once they have passed a certain point in their development, for example, those that may have extensive genetic changes.11
In contrast to the stable or increasing incidence of anal cancer, the data on the relationship between ART, AIN, and anal HPV infection are inconsistent in the literature, as described well by Van der Snoek et al. Some authors have shown a continued high prevalence of HGAIN and oncogenic HPV infection among individuals in the ART era,12–15 and others have shown reduced prevalence of anal HPV infection or increased regression of HGAIN.16–18 It is noteworthy, however, that even in those studies that show statistically significant benefit of ART for AIN or HPV infection, that benefit is typically limited in terms of the proportion of participants showing increased clearance of HPV infection or disease or reduced incidence.
Thus, it is important to continue to gather new data, particularly as new forms of ART are introduced, the threshold for initiating ART changes, and as HIV-infected individuals remain on ART for progressively longer periods of time. ART has continued to evolve since 1996 in terms of efficacy and ease of use; individuals starting ART at present may experience more sustained and pronounced HIV viral load suppression than those initiating ART when first introduced in the 1990s. In some studies, lower nadir CD4 level is associated with increased risk of HGAIN,16 and because of studies showing better outcome for HIV disease, ART is now being initiated at higher CD4 levels than in the past. The benefits of these new developments for ART-associated immune response to HPV and incidence or clearance of AIN are not known.
The recent results of Van der Snoek et al. are therefore of great interest, suggesting that ART use is associated with reduced risk of AIN. However, the study does have some limitations, including its cross-sectional design. The article does not address the effect of ART on HGAIN specifically, as the size of the study was limited, and only a small proportion of those with AIN had HGAIN. The prevalence of HGAIN in their cohort was lower than that seen in some American cohorts, and with a median nadir CD4 of 229 × 106 cells/L and median CD4 count of 490 × 106 cells/L, it seems unlikely that their underlying immune status explains this difference. As acknowledged by the authors, it is possible that they underestimated the true prevalence of HGAIN in their cohort. The investigators performed a limited number of biopsies on each participant who had a visible lesion on HRA, on average, about 1 biopsy per participant. Data from the cervical literature show that the severity of disease is more likely to be accurately determined when more, rather than fewer, biopsies are performed.19 When training providers in HRA, we recommend that multiple biopsies be performed when assessing a patient for the first time. Anal cytology was not performed and might have revealed the presence of HGAIN in additional participants. It is also possible that ART may have led directly or indirectly to fewer lesions, or smaller size of lesions, rendering them more difficult to detect at HRA.
The authors also show that ART use was associated with a lower prevalence of anal HPV infection. However, these results must also be interpreted with caution, as even with the “reduction,” >88% of the men on ART had anal HPV infection. A higher proportion of the ART-treated men had HPV 16 infection than the untreated men, a poor harbinger for long-term cancer risk since HPV 16 is the most common type in anal cancer. Infection with multiple HPV types was found in 65%, and among all participants who were HPV positive >75% had at least 1 oncogenic type. As described by the authors, it is likely that many of these reflect persistent HPV infections. The low prevalence of AIN in the context of a high prevalence of anal HPV infection is consistent with the possibility that the authors may have underestimated the true prevalence of AIN, including HGAIN.
In the absence of a clear picture of the benefits of ART, what should we be doing now? Even if ART might positively influence the natural history of AIN, there are currently insufficient data to initiate ART based on HPV-related disease status. Until additional data are available, this decision should remain based on the criteria recommended by relevant professional societies (available at: http://aidsinfo.nih.gov/guidelines/).
One clear action item: we must do everything possible to prevent anal cancer. Primary prevention through vaccination against HPV 16 and 18, the most common HPV types in anal cancer, offers great promise for those who have not yet been exposed to these HPV types.20 Vaccination with the quadrivalent HPV vaccine is approved for prevention of genital warts, AIN, and anal cancer. It is now routinely recommended for boys and men aged 9 to 21 years and up to 26 years of age for HIV-positive males. Vaccination with the bivalent or quadrivalent vaccines is routinely recommended for girls and women aged 9 to 26 years, and the quadrivalent vaccine is also approved for prevention of AIN and anal cancer in women.
Unfortunately, vaccine uptake currently remains limited in the target age-groups, and many men and women have already been exposed to HPV, particularly those aged >26 years. For these individuals, secondary prevention, consisting of screening for and treating HGAIN may play an important role in reducing the incidence of anal cancer. We urgently need to study the efficacy of secondary prevention since this is not yet proven. If secondary prevention is shown to reduce the incidence of anal cancer, routine screening and treatment of HGAIN among those at risk for anal cancer should become standard of care. At the University of California San Francisco Anal Neoplasia Clinic, we, along with many others, choose to treat patients with HGAIN until we have those data. This is based on the high incidence of anal cancer in at-risk populations including those with HIV infection; strong similarities between anal and cervical cancer and their precursors; the demonstrated success of cervical cancer prevention programs; the data, albeit limited, showing that a high proportion of HGAIN lesions can be treated using office-based procedures21–24; and earlier studies suggesting that anal screening and treatment in targeted populations could be performed in a cost-effective manner.25,26
Regardless of data on the effect of ART on anal HPV infection and HGAIN, let's not forget that the current incidence of anal cancer among HIV-infected MSM remains unacceptably high. Anal HPV infection is not clearing in most patients, and HGAIN remains common. It is not yet clear whether the post-ART increase in anal cancer will continue or whether long-term ART use will eventually lead to a reduction in anal cancer. What is clear is that the problem of anal cancer, a potentially preventable disease, will not be going away soon.
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