Progress and Pitfalls in Defining the Influence of Highly Active Antiretroviral Therapy on Human Papillomavirus—Associated Cervical Disease

The results of the study reported by Minkoff, et al in this issue of the Journal [1] provide important new information to the continued debate on whether immune deficiency is responsible for the increase in human papillomavirus (HPV) infections, cervical squamous intraepithelial lesions (SILs), and cervical cancers among HIV-infected women [2, 3]. Evidence that the increase in two other AIDS-defining malignancies, Kaposi’s sarcoma (KS) and non-Hodgkin lymphoma (NHL), is due to immune deficiency is clear. The standardized incidence rate of these cancers is orders of magnitude higher among individuals with HIV/AIDS, and increased risk has been well documented with more advanced immune deficiency manifest as lower CD4 cell counts. Importantly, the rates of KS and NHL declined substantially in the HAART era, suggesting that restoration of human herpesvirus 8 (HHV-8) and Epstein Barr Virus (EBV) immunologic control was sufficient to reduce the risk of these virally-associated malignancies [4, 5]. The influence of immune deficiency on the risk of HPV and associated neoplasia has been less clear. The standardized incidence rate comparing persons with HIV/AIDS to the general population shows a more modest difference compared to KS and NHL [3, 4]. It can be argued that the moderately elevated rates of cervical cancer among HIV-infected individuals reflect simply a common shared behavior (e.g., increasing number of lifetime sexual partners). However, invasive cervical cancer rates are higher among renal transplant patients who would presumably be unlikely to report higher rates of sexual exposure to viral infection compared to the general population [6]. In addition, natural history studies have shown convincing evidence of an independent association between CD4 cell count and HIV load with an increase in HPV squamous intraepithelial lesions (SIL) incidence and persistence [7]. Based on these data, it would have been predicted that HPV and SIL prevalence and incidence would decline in the HAART era; unfortunately the results of early studies that evaluated this have been inconsistent [8–13]. Several factors are likely to have influenced the validity of these prior studies of HAART on HPV and SIL natural history. Predominant is the inherent non-comparability of women in whom HAART is initiated compared to those who are not placed on treatment. Because women that initiate HAART are more likely to have advanced HIV disease, with lower CD4 cell counts and higher HIV loads, than women in whom HAART is not initiated, true effects of treatment could be substantially attenuated. Furthermore, adherence to, and effectiveness of, treatment were often not ascertained, which could further attenuate the ability to observe true treatment effects. The analysis by Minkoff, et al. clarifies some of the prior inconsistencies by using a study design that allowed each woman to be used as her own control, comparing HPV and SIL outcomes in periods before and after HAART initiation. This design potentially allows for a more precise evaluation of the possible biological effect of HAART on HPV and SIL outcomes. Using this design, the authors demonstrated a reduced prevalence and incident detection of high-risk (HR) HPV and a lower prevalence and persistence of HR-HPV positive SILs [1] among women who initiated HAART during follow-up in the Women’s Interagency HIV Study (WIHS) compared to these measures during their own pre-HAART initiation observation. Among the women selected for this analysis, adherence to, and effectiveness of, HAART were highly correlated, and around one-half of those initiating treatment were considered non-adherent and/or had an ineffective virological response to HAART. The impact on HPV incidence and HR-HPV+ SIL clearance was reduced among women with non-adherent or ineffective use, again suggesting a biological effect of HAART on HPV and SIL natural history. Although the study design employed here improves the ability to look at this question, limitations remain. The clinical decision to initiate HAART is complex, and patients deemed unlikely to remain adherent to therapy (e.g., unable to keep clinic appointments, active injection drug use), are less likely to be placed on therapy. Further, initiation of HAART among HIV-infected persons has been widely recognized as a life-altering event. Women who begin HAART may make other changes to improve their health and modify their behavior at the same time (such as reduction in illicit drug use or risky sexual behavior or increased smoking cessation), which could potentially exaggerate a true effect of HAART immune restoration. While the inclusion of only women initiating HAART and using pre-HAART data from those women as their own control attempt to minimize confounding by selection into treatment, they do not control for behaviors that may change as a result of HAART initiation. The authors explored the impact of some key risk factors for HPV/SIL incidence and clearance (e.g., recent sexual behavior, smoking) and reported no impact on the overall results. However, the risk of residual confounding from unmeasured factors remains. Further, the same selection factors the investigators attempted to avoid because they may influence antiretroviral initiation may still be at play in comparisons of adherent to non-adherent participants or virological responders to non-responders. Despite these theoretical limitations to the current study, the results likely reflect important clinical and public health consequences of the adherent and effective use of HAART. The authors provide an equivocal perspective; on the one hand, the observed impact of HAART on reducing incident HPV detection and SIL persistence may be expected to reduce cervical cancer rates, while on the other hand, increased survival on HAART may increase cervical cancer rates as women are aging into the groups with higher cervical cancer incidence. Are the observed stable rates of cervical cancer among HIV-infected women the result of these competing influences? We caution against using cervical cancer incidence as the primary metric to evaluate the potential population level impact of HAART. Early detection and treatment of SIL has a profound impact on invasive cancer rates. According to current guidelines, HIV-positive women should be screened twice in the year following HIV diagnosis, and then annually thereafter unless abnormalities are diagnosed. A recent study reported that 25% of HIV-positive women reported not having a Pap smear in the last year [14], which was comparable to data showing that up to 20% of women in the general population report no screening in the previous 3 years [15, 16]. While it is important to remain vigilant about cervical cancer screening in HIV-positive women, these data suggest that comparable proportions (75–80%) of HIV-infected and HIV-uninfected women are complying with the respective screening guidelines. If these populations are equally likely to be appropriately treated for cervical intraepithelial neoplasia (CIN), then the increase risk of cervical cancer among the HIV- infected women will never be manifest, due to appropriate early detection and treatment. Therefore, any influence of HAART on cervical cancer rates could be masked. Unfortunately, little information is available comparing the frequency of CIN treatment among HIV-positive and HIV-negative women. These data will be critical for understanding the period effects on cervical cancer incidence, as it is both possible that HIV-infected women are less compliant with follow-up of abnormal Pap results and resulting inadequate treatment of diagnosed CIN grades 2/3 (CIN2/3), or conversely, that because of their higher risk, they are more aggressively managed even for persistent low grade CIN1 [17]. Only large collaborative studies with rich data on cervical dysplasia screening and management and rigorous consideration of statistical approaches will be able to fully address this important issue. For the reasons presented, the impact of HAART on HPV-related disease remains more clearly observable when evaluating SIL of any grade as the primary outcome, as was done in the present cohort study by Minkoff, et al. Pap-smear diagnosed SIL in the HIV-infected women are mostly low grade (LSIL), with high-grade SIL (HSIL) relatively uncommon (<4% cumulative incidence over 10 years) [17]. Although the risk of HSIL (and by extension cervical cancer) is relatively increased in HIV-infected compared to HIV-uninfected women, the absolute risk is substantially lower than that observed for HPV DNA detection and LSIL. Since referral to colposcopy and biopsy is triggered following any SIL diagnosis, and this follow-up comprises a significant burden to both the patient and the health care system, perhaps the most profound implication of the results presented Minkoff, et al. is that effective and adherent HAART use can be expected to reduce SIL prevalence, and therefore potentially reduce the number of colposcopic referrals and unnecessary biopsies/treatment in the treated women.