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Adv Dent Res 19:99-105, April, 2006
© 2006 SAGE Publications
Biology of HPV in HIV Infection
Presented at the Fifth World Workshop on Oral Health and Disease in AIDS, Phuket, Thailand, July 6–9, 2004, sponsored by Prince of Songkla University, Thailand, the International Association for Dental Research, the World Health Organization, the NIDCR/National Institutes of Health, USA, and the University of California-San Francisco Oral AIDS Center.
J. Palefsky
Departments of Medicine and Stomatology, 505 Parnassus Ave Room M1203, Box 0126, University of California San Francisco, San Francisco, CA 94143-0126, USA; joelp{at}medicine.ucsf.edu.
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Abstract
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HIV-positive men and women are at increased risk of anogenital and oral HPV infection. The risks for HPV-associated high-grade intra-epithelial neoplasia (IN) and cancer are also increased. The prevalence of oral, anal, and cervical HPV infection in HIV-positive individuals compared with HIV-negative individuals increases with progressively lower CD4+ levels, as does incident high-grade IN. In contrast to IN, development of cancer is not related to lower CD4+ level. With increasing grades of IN and cancer, the proportion of tissues with copy-number abnormalities (CNA) increases, with one of the most common genetic changes being amplification of chromosome 3q. The presence of CNA is associated with the integration of HPV DNA into the host genome, with loss of HPV E2 and/or E2 rearrangement. This suggests a link between CNA and increased HPV-induced chromosomal instability mediated through de-repressed E6 and E7 expression consequent to loss of functional E2 protein. In addition, epigenetic changes occur with increasing frequency in high-grade IN and cancer, such as hypermethylation leading to down-regulation of potential tumor suppressor genes. Analysis of these data together suggests that immune suppression plays a more prominent role in the earlier stages of HPV-associated disease, up to and including incident high-grade IN. Persistent high-grade IN and development of cancer may be more strongly related to the cumulative effect of HPV-associated genetic instability and the resulting host genetic changes. There are few data to suggest a direct role for HIV in the pathogenesis of HPV-associated neoplasia, but HIV-associated attenuation of HPV-specific immune responses may allow for persistence of high-grade IN and sufficient time for accumulation of genetic changes that are important in progression to cancer.
Key Words: Virus • HPV • HIV • intra-epithelial neoplasia • CD4
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The Prevalence and Incidence of HPV Infection and HPV-associated Disease in HIV-positive Men and Women
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One of the key risk factors for HPV acquisition is number of sexual partners. It is therefore not surprising that individuals infected with HIV have a high prevalence of anogenital infection with HPV as well, given the overlap in risk factors for HIV infection. In the pre-HAART era, nearly all HIV-positive men who had sex with men were shown to have anal HPV infection, usually with multiple HPV types (Critchlow et al., 1992; Palefsky et al., 1998a). HIV-positive women have been shown to have a high prevalence of cervical HPV infection (Sun et al., 1995; Cu-Vin et al., 1999; Ahdieh et al., 2000, 2001; Duerr et al., 2001), and several studies have shown that they have a high prevalence of anal HPV infection as well (Melbye et al., 1996; Palefsky et al., 2001a; Durante et al., 2003). Likewise, oral HPV infection has been shown to be common among HIV-positive men and women (Hagensee et al., 2004; Kreimer et al., 2004). In one recent study, high-risk HPV infections were present in nearly 14% of oral-rinse specimens from HIV-positive individuals (Kreimer et al., 2004) with risk factors including having more than one oral sex partner in the previous year.
HPV can also be detected in the absence of sexual risk factors, e.g., anal HPV infection in HIV-positive women and men with no history of receptive anal intercourse (Palefsky et al., 2001a; Piketty et al., 2003), suggesting that it may also be acquired at a given site through spread from other genital sites or through fomites (Melbye et al., 1996; Palefsky et al., 1998a, 1999; Strickler et al., 2003, 2005), suggesting means such as fingers or sex toys. Recent evidence suggests that about half the HPV infections in HIV-positive women can be accounted for by recent sexual acquisition, whereas the other half most likely represents re-activation of previously acquired HPV types (Strickler et al., 2005). There is a clear relationship between progressively lower CD4+ level and increased detection of HPV types in the anus and cervix. More advanced immunosuppression may be associated with increased HPV replication, increasing the likelihood that a given HPV type will be detected (unpublished observations). Interestingly, this relationship was not as pronounced for HPV16 in the cervix as for other oncogenic HPV types, primarily because HPV16 was detected at higher frequency in women with high CD4+ levels than were the other types (Strickler et al., 2005). Analysis of these data suggests that HPV16 may be handled less efficiently by the immune system than the other types, and this may provide an explanation for why HPV16 is the most common oncogenic HPV type in the healthy, HIV-negative population.
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Prevalence of HPV-associated Diseases
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Consistent with the high prevalence of anogenital HPV infection in HIV-positive individuals, the prevalence and incidence of HPV-associated anogenital disease were high in the pre-HAART era. Cervical intra-epithelial neoplasia (CIN) was shown to be more common among HIV-positive than HIV-negative women (Sun et al., 1995; Maiman et al., 1998; Massad et al., 1999; Duerr et al., 2001). Anal intra-epithelial neoplasia (AIN) was also shown to be more common among HIV-positive men (Critchlow et al., 1995; Palefsky et al., 1998b,c; Piketty et al., 2003) and women (Holly et al., 2001; Durante et al., 2003) than in their HIV-negative counterparts. Interestingly, there are few data to indicate that the prevalence or incidence of oral dysplastic lesions is increased among HIV-positive men and women compared with HIV-negative men and women, although the prevalence of oral warts is clearly increased, particularly since the introduction of HAART (Greenspan et al., 2001, 2004).
As with HPV infection, one of the most consistent risk factors for anogenital IN was a lower CD4+ level, suggesting that HIV-related immune suppression, as reflected by CD4+ levels, was playing an important role in disease pathogenesis (Critchlow et al., 1995; Palefsky et al., 1998b; Frisch et al., 2000). Finally, consistent with the HPV and IN data, the incidence of cervical and anal cancer has been shown to be elevated in HIV-positive men and women (Frisch et al., 2000). HIV-positive men were shown to be at nearly 37-fold higher risk of anal cancer than the general population, and HIV-positive women were shown to be at five-fold and nearly seven-fold risk of cervical and anal cancer, respectively, compared with the general population. Tonsillar cancer, which is strongly associated with HPV (Mellin et al., 2000), was also shown to be nearly threefold more common in HIV-positive men than in the general population. However, in contrast to the clear relationship between IN and lower CD4+ level, the relationship between advanced immunosuppression and invasive cancer is not as apparent (Goedert et al.,1998). In another study, the increasing risk for the most advanced pre-cancerous IN, carcinoma in situ, was not accompanied by a similar increase for invasive cancers (Frisch et al., 2000). Analysis of these data suggests that the latest stages of the natural history of HPV-associated cancers, i.e., progression to cancer, are not greatly influenced by the immune system.
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Effect of HAART Therapy on HPV Lesions
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In contrast to the clear beneficial effect of highly active anti-retroviral therapy (HAART) on the incidence of Kaposi’s sarcoma and non-Hodgkins lymphoma, the emerging data on the effect of HAART on the natural history of HPV-associated anogenital neoplasia and cancer present a mixed picture. In part, this may reflect differences in study design and outcome measures between studies (Heard et al., 2004). It may also reflect unmeasured confounders such as ‘selection by indication’, in which HIV-positive individuals are likely to have more advanced anogenital disease a priori, given that HAART is often initiated only when the CD4+ level declines to below 350/mm3. In the cervix, HAART has been shown, in some studies, to reduce progression to high-grade CIN, and to increase regression to normal (Heard et al., 2004). However, a substantial proportion of HIV-positive women continue to progress to high-grade CIN in those studies. No studies have shown an effect of HAART on cervical HPV positivity, and while some studies have shown a higher rate of regression of high-grade CIN among women on HAART than in women not on HAART, many women have persistent high-grade disease. The effect of HAART on AIN is even less impressive than in the cervix. Studies show little (Piketty et al., 2004; Palefsky et al., 2005) or a modest (Wilkin et al., 2004) effect of HAART on prevalent AIN, and one study has shown no effect on regression of high-grade AIN (Palefsky et al., 2001b). Consistent with these data, the incidence of anal cancer has continued to increase since the widespread introduction of HAART in 1996 (Cress and Holly, 2003; Bower et al., 2004). Finally, like anal disease, HAART appears to have little beneficial effect on HPV-associated oral disease. Several studies have in fact shown that oral warts worsen after HAART initiation (Greenspan et al., 2001, 2004).
Analysis of the data, taken together, suggests that loss of immune response to HPV may play its most important role in permitting the development of high-grade IN, which has the potential to progress to cancer. However, progression from high-grade IN to cancer may depend on other factors. Increasing evidence suggests that one of these factors may be changes in host gene expression secondary to HPV-induced chromosomal instability and copy-number abnormalities (Fig. 1 ).
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Fig. 1 - Pathogenesis of HPV-associated neoplasia and effect of highly active antiretroviral therapy (HAART). Most individuals are assumed to acquire HPV infection early after the initiation of sexual activity, and may acquire HIV infection sometime thereafter. Infection with multiple HPV types may occur, but as long as HIV-associated immunosuppression remains minimal, there is good control of HPV replication and little anogenital disease. As HIV-associated immunosuppression progresses, there is increased HPV replication and the development of IN 1 or IN 2-3. Progression from IN 2-3 to invasive cancer may take many years or decades, in which the key progression events are driven by host genetic change. Less-advanced immunosuppression and early stages of IN may therefore respond to the initiation of HAART, due to the restoration of HPV-specific immune responses. The beneficial effect of HAART may be less pronounced by the time an individual is diagnosed with IN 2-3, either because HIV-associated immune response has been damaged so severely that immune restoration due to HAART fails to restore HPV-specific immunity, or because a proportion of IN 2-3 has accumulated sufficient genetic changes by the time of HAART initiation that HAART-associated restoration of HPV-specific immunity is insufficient by itself to lead to lesion regression. In this model, HIV-associated immune suppression plays a key role in the pathogenesis of cancer by allowing IN 2-3 lesions to persist long enough to allow sufficient time to accumulate the genetic changes necessary for progression to cancer.
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Mechanisms of Potentiation of HPV-associated Disease in HIV-positive Individuals
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Several mechanisms may explain the increased prevalence and more aggressive course of HPV-associated disease in HIV-positive individuals. These include direct interactions between the two viruses and, as described above, attenuated immune response and chromosomal instability. HIV may interact with HPV at the molecular level through the action of the HIV-1 tat protein, which has been shown to transactivate the HPV long control region in vitro, leading to increased expression of the HPV E6 and E7 oncogenes (Vernon et al.,1993). However, there is no evidence for permanent infection of anogenital or oral epithelium where HPV resides, and no evidence for co-infection in HPV-infected keratinocytes. Further, while co-infection is not necessary per se, since the HIV-1 tat protein may be secreted from HIV-infected cells and taken up by HPV-infected keratinocytes, the HIV-1 tat protein has never been demonstrated in HPV-infected epithelium in vivo. It is therefore unlikely that the two viruses interact directly in a sustained manner that would be expected to modify the outcome of HPV-associated disease.
(1) Modulation of the Immune Response
Modulation of the immune response to HPV is a more likely mechanism by which HIV potentiates HPV-associated disease. The immune response to HPV is believed to play a critical role in the control of HPV infection in both healthy and HIV-positive individuals. HPV infection is the most common sexually transmitted infection, with approximately 75% of sexually active adults acquiring one or more genital HPV types during their lifetime. However, most women become HPV-negative after the age of 30 years, as determined by the currently available HPV detection tests, and only a small proportion of healthy individuals are diagnosed with a lesion, particularly high-grade disease or cancer (Schiffman, 1992). These are presumably due to the generation of an effective cell-mediated immune response to HPV. Conversely, women with a history of organ transplantation have an increased incidence of cervical and vulvar cancer compared with healthy women, presumably due to attenuated immunity associated with medication to prevent graft rejection (Penn, 1986, 1991a,Penn, b). Experience with HIV mirrors this experience.
Little is known about the precise nature of this immune response; some studies have demonstrated that T-cells cytotoxic to the HPV E6 or E7 oncogenes may be important (Kadish et al., 1994, 1997; Nakagawa et al., 1996, 1997, 1999; Tsukui et al., 1996). It is clear, however, that the systemic immune response to HPV is relatively weak compared with that to systemic viruses such as cytomegalovirus (Jacobson et al., 2001; Komanduri et al., 2001), presumably because of the highly compartmentalized nature of HPV infection, with HPV infection restricted to epithelial cells. Through its effect on CD4+ cells and regulation of immune responses to a variety of antigens, HIV infection may attenuate the systemic immune response to HPV. It is speculated that if there is a low number of circulating HPV-specific memory cells, then HPV-specific immunity may be particularly vulnerable to the effects of HIV. Moreover, HPV-specific immunity may not recover fully after immune response is restored, which may explain the relatively limited beneficial effect of HAART on HPV-associated lesions.
(2) Local Immunity
Local immune response at the tissue level may be especially important, but this has been difficult to study. Levi et al.(2005) showed that the number of Langerhans cells is diminished in women with higher HIV viral load, in CIN lesions of HIV-positive women, compared with HIV-positive women. Kobayashi et al.(2004) have shown that, in CIN in HIV-positive women, immune cell densities (CD4+ T-cells, macrophages, neutrophils, and natural killer cells) and expression of interferon-gamma were significantly decreased compared with CIN in HIV-negative women. Regulatory cytokines were also down-regulated in HIV-positive women. Analysis of these data indicates that both pro- and anti-inflammatory responses present in high-grade CIN lesions are suppressed in HIV-seropositive women (Kobayashi et al., 2004).
HIV infection may also be associated with perturbations in circulating cytokines, which in turn may modulate HPV infection at the tissue level. Elevated levels of circulating monokines—including IL-6, IL-1, and TNF alpha—have been described in HIV-1 infection (Takeshita et al., 1995), and these and other cytokines have also been shown to modulate HPV transcription (Woodworth et al., 1990, 1992, 1995; Woodworth and Simpson 1993; Iglesias et al., 1995; Gaiotti et al., 2000).
(3) Genetic Instablility
As described previously, immune response appears to have a limited role in protection against the progression of high-grade lesions to invasive cancer. If so, then other non-immune factors must be operative. There is now increasing evidence to suggest that progression to cancer may reflect genetic damage in the lesions. At advanced stages of disease pathogenesis, it is possible that these genetic changes have reached the point where they have rendered the lesion resistant to any immune reconstitution that may be brought about by HAART.
In vitro studies with cervical cell lines have indicated that the oncogenic properties of high-risk HPV types can be attributed mainly to two HPV proteins, the HPV E6 and E7 proteins. These proteins disrupt DNA repair and cell-cycle control through interaction with the tumor suppressors p53 and RB, respectively (Dyson et al., 1989; Munger et al., 1992). E6 and E7 have been shown to induce genomic instability in cell culture (Solinas-Toldo et al., 1997; Duensing et al., 2000; Duensing and Munger 2001), and chromosomal copy-number imbalance has been described previously for both cervical and anal cancer (Heselmeyer et al., 1997; Kirchhoff et al., 1999; Hidalgo et al., 2000; Skyldberg et al., 2001).
Several studies have shown that HPV DNA is integrated into the host cell genome at increasing frequency with the progression of CIN to cervical cancer (von Knebel Doeberitz, 2002). This is important, because integration is associated with loss of function of the HPV E2 protein (Fig. 2). Under normal conditions, the E2 protein binds to E2 binding sites in the HPV long control region, leading to repression of expression of E6 and E7 (Sang and Barbosa, 1992; Nishimura et al., 2000). HPV normally exists as a double-stranded circular episome, and to integrate into the human genome, it must linearize (Fig. 2). When HPV linearizes, it typically does so by disruption in the E2 open reading frame. Integration may therefore lead to lower levels of E2 expression, with loss of E2-mediated repression of E6 and E7 expression. This, in turn, may lead to increased chromosomal instability through the actions of E6 and E7.
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Fig. 2 - Role of HPV integration and chromosomal instability in pathogenesis of anogenital cancer. HPV normally exists as a circular episome in low-grade lesions, but the proportion of tissues with HPV DNA in the host genome increases with increasing severity of IN and invasive cancer. When HPV integrates, linearization of the viral genome usually occurs with disruption of the E2 open reading frame, leading to loss of E2 function. E2 primarily serves to repress expression of the HPV E6 and E7 oncogenes. Since the E6 and E7 proteins contribute to chromosomal instability, de-repressed expression of E6 and E7, consequent to the loss of E2 function upon HPV integration, may contribute to increased chromosomal instability. Over time, in conjunction with other factors that lead to host genetic changes, such as environmental DNA-damaging agents and epigenetic changes, progression to invasive cancer may occur.
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Analysis of Genomic Alterations
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An increasing number of technologies has recently been developed to allow for the large-scale analysis of genomic alterations in cancer tissues. Solid tumors usually present with complex chromosomal re-arrangements, leading to multiple DNA copy-number imbalances (Albertson and Pinkel, 2003). Copy-number abnormalities (CNAs) affect host gene expression when there is over-expression of a potential oncogene in amplified regions, or loss of a potential tumor suppressor in regions that have been deleted. CNAs in AIN lesions from HIV-positive individuals have been described by comparative genomic hybridization (CGH) (Haga et al., 2001). In that study, the proportion of AIN tissues with genetic changes significantly increased with the severity of the histopathologic grade. No tissues diagnosed as AIN 1 had CNA, whereas 5 of 17 (29%) diagnosed with AIN 2 and 5 of 9 (56%) diagnosed with AIN 3 showed genetic changes (p = 0.02). The most common regional DNA copy-number change was gain mapped to chromosome arm 3q. This finding was of interest, since this alteration was previously reported to be among the most common alterations in cervical cancer (Umayahara et al., 2002), suggesting a common molecular pathway for these two HPV-associated anogenital neoplasias.
While CGH has been particularly useful for genome-wide identification of large regions of DNA CNA (Kallioniemi et al., 1992), the utility of this metaphase chromosome-based methodology has been hampered by its low resolution (from 5 to 15 MB), resulting in investigators’ inability to detect small regions of CNA. A more recent study of copy-number abnormalities used a technique known as ‘microarray-based CGH’ (Pinkel et al., 1998: Pollack et al., 1999). This technique permits a higher-resolution genome-wide analysis of CNAs than does standard CGH. With this technique, the most common gains in AIN tissues were on chromosome arms 1p, 1q, 3q, 8p, and 20q (Gagne et al., 2005). Amplification of chromosome 3q was found in 70% of AIN biopsies with CNA. The most common regions of loss were on chromosome arms 2q, 7q, 11p, 11q, and 15q. The detection of a 3q gain in over 70% of AIN with CNA suggested that this copy-number gain is an early event in the tumorigenesis process of AIN. This result is in contrast to a previous finding, in cervical cancer, that 3q gain was associated with a later stage, i.e., transition to invasive cancer (Heselmeyer et al., 1996). However, a later report showed that 3q gain was commonly detected in CIN 2 (6/13) (Kirchhoff et al., 1999). In the study by Gagne et al.(2005), HPV16 DNA integration or re-arrangement correlated with CNA in host cell DNA (p = 0.007), consistent with the model in which loss of E2 contributes to chromosomal instability.
Although aCGH can resolve amplicons at the one- to two-megabase regional resolution, the most common alteration on chromosome 3 could be resolved only to a 75-Mb region from 3q21-qtel, suggesting that there may be several oncogenes in this region that function cooperatively in the progression to high-grade AIN and possibly cancer. In the large region found to be amplified in the AIN biopsies, from 3q21 to 3qter, 30 genes have been reported to serve as proto-oncogenes and/or were shown to be increased in various cancers. The TP73L gene, located at 3q28, encodes a P53-like product that lacks a transactivation domain and can serve as dominant-negative for P53, thus acting as an oncogene. H-RYK (3q22.2) has been shown to be overexpressed in ovarian tumors (Katso et al., 2000). It is a member of the receptor tyrosine kinase family that has been shown to activate the mitogen-activated protein kinase (MAPK) pathway (Katso et al., 1999). In the 3q region, there also are 3 genes that are associated with the AKT pathway: MRAS, a RAS-related protein (3q22.3); and PIK3CB (3q22.3) and PIK3CA (3q26.32), the two subunits of phosphoinositide-3-kinase. The AKT pathway signals control of apoptosis through BCLX, the caspase cascade, and/or NF-kappa B control (Chang et al., 2003). The AKT pathway has also recently been shown to activate hTERT to induce telomerase activity (Kimura et al., 2004), a finding that is of interest, since E6-mediated induction of telomerase activity has been shown to be important in vitro for HPV-associated immortalization (McDougall, 2001). The AKT pathway has also been implicated in the pathogenesis of other HIV-associated malignancies, including Kaposi’s sarcoma (Sodhi et al., 2004).
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Other Mechanisms
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In addition to CNA, epigenetic mechanisms may affect gene expression. This includes methylation of gene promoter regions, leading to down-regulation of expression of those genes. IGSF4 is a tumor suppressor gene whose promoter has been shown to be methylated in nearly two-thirds of cervical cancers (Li et al., 2005). In another recent study, Gustafson et al.(2004) reported that there was increased methylation with the increased severity of CIN, and the mean number of methylated genes was significantly higher in high-grade lesions compared with low-grade lesions or normal cervical tissues. Other genes methylated with greater frequency included DAPK1 and HIC1. Similar findings of increased methylation in association with increased grade of CIN were reported by Widschwendter et al.(2004). It has not yet been determined if methylation occurs more frequently in lesions of a given grade in HIV-positive individuals, compared with HIV-negative individuals, as a mechanism to explain the higher incidence of high-grade disease among the former.
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An Integrated Model of the Pathogenesis of HPV-related Disease in the HIV-positive Host
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Development of IN and progression to invasive cancer are clearly multifactorial processes in HIV-positive individuals. Analysis of accumulating data from both the pre-HAART and post-HAART eras suggests that the loss of immune response to HPV is a key factor in the increased prevalence and incidence of IN. There is currently no evidence to suggest that HPV behaves differently in the HIV-positive host. Instead, it seems likely that a key difference between HIV-positive and HIV-negative individuals is that, among the former, lesions are likelier to persist, given the attenuated immune response. In this model, persistence of high-grade IN is a key factor in the progression to invasive cancer (Fig. 2 ). Transition of dysplastic epithelial cells to a fully malignant phenotype may represent the cumulative effect of multiple genes and changes in levels of their expression, perhaps akin to the role of cumulative genetic changes in progression from benign colonic adenomas to invasive colon cancer (Vogelstein and Kinzler, 1993). The development and accumulation of CNA and other changes in host gene expression require time. The inability of the immune system in the setting of HIV infection to clear HPV-infected cells in the anogenital or oral epithelium might serve a facilitating function by providing HPV-infected cells with ample time for these changes to accumulate. The relatively limited beneficial effect of HAART might therefore be explained by one of two possibilities: (1) The damage that occurred to the immune system led to an irreversible loss of HPV-specific immune response, despite improvement in response to other agents or antigens; or (2) sufficient genetic damage may have occurred in the epithelium that the cells continue to proliferate even if HPV-specific immunity is restored.
The factors that lead to genetic changes are poorly understood; HPV probably plays a major role through E6-mediated chromosomal instability, but it is likely that other factors play a role as well. There is no evidence to suggest that HIV plays a direct role in this process, but environmental carcinogens may induce genetic damage, e.g., tobacco-related carcinogens, and it has been shown that smoking is a risk factor for both anogenital and oral cancer (Winkelstein, 1990; Minkoff et al., 2004). Dietary factors that affect DNA integrity and the generation of free radicals may play a role. Some of the drugs commonly included in a HAART regimen, such as AZT, may have DNA-damaging effects, and it is an open question as to whether HAART itself may contribute to malignant transformation, particularly in the setting of use over a prolonged time period.
Further research is needed to determine if any or all of the elements of this model are accurate. If shown to be accurate, however, this model has important implications. If HAART has any beneficial effect on HPV-related disease, it would be expected primarily in the form of reducing incidence of disease among those with no disease at the time of HAART initiation. For those who already have IN at the time of HAART initiation, HAART would also be expected to be most effective if the lesion is low-grade or relatively recent in development. Those who begin HAART at a higher-nadir CD4+ level would also be expected to benefit more, since it is possible that irreversible damage may already have occurred in many individuals by the time their CD4+ level drops below 350/mm3, the level at which initiation of HAART is often recommended. HAART would also be predicted to have different effects depending on the grade of IN at the time the individual initiates HAART. Low-grade disease might respond well to HAART-associated immune restoration with regression to normal, and the incidence of IN among those with no disease at the time of HAART initiation might be expected to decline to levels closer to those of HIV-negative individuals. However, at the other end of the spectrum, high-grade IN might not undergo regression after HAART initiation, and the incidence of anogenital cancer might not decline. The incidence of anal cancer in particular would actually be predicted to increase under this scenario, since individuals with high-grade AIN are living longer on HAART, and they might have increased time to progress to invasive cancer in the absence of routine screening and treatment. The impact on cervical cancer would be expected to be less dramatic in those locations where screening and treatment of CIN are routine.
In the absence of a clear benefit of HAART, it is also clear that individuals on HAART require careful follow-up to exclude HPV-related IN, and careful follow-up after treatment. AIN presents a special problem, since there are currently no standardized screening or treatment guidelines for this disease. Further research is clearly needed in this area. Finally, the extraordinarily high prevalence of high-grade AIN presents special challenges, given the difficulty of removing large sections of the anal mucosa without inducing excessive morbidity. A more complete understanding of the molecular pathways that underlie progression of high-grade IN to invasive cancer would be of great importance in the identificationn of the genetic markers that signify an individual as being at particularly high risk of progression to cancer, and therefore in need of aggressive monitoring and therapy to prevent the development of cancer. Identification of these markers will also benefit those with HPV-related neoplasia at other sites, including the cervix and oral cavity.
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Acknowledgments
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This work was supported by grants CA54053 and DE07946, the AIDS Malignancy Consortium grant UO1 CA70019, and the AIDS and Cancer Specimen Resource grant U01 CA66529. Some of the cited studies were carried out in the General Clinical Research Center, University of California, San Francisco, with funds provided by the Division of Research Resources 5 M01-RR-00079, US Public Health Service.
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Advances in Dental Research, Vol. 19, No. 1,
99-105 (2006)
DOI: 10.1177/154407370601900120
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Abstract
The Prevalence and Incidence...