Thursday, June 1, 2023
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Human papillomavirus (HPV) has been associated with invasive cervical cancer and with the advanced precursor lesions cervical intraepithelial neoplasia (CIN) grades 2 and 3.[1,2] Multiple types of HPV have been identified, including HPV-6 and HPV-11, which are associated with viral condyloma or mild dysplastic changes (CIN I) and which do not progress to frank neoplasia.[3] In contrast, HPV types 16, 18, 31, 33, and 35 are often associated with more advanced precursor lesions and are found in the majority of cases of invasive carcinoma.[4,5]
Abnormal Papanicolaou (Pap) smears are relatively common among HIV-infected women. Thus, in the Women's Interagency HIV Study (WIHS) sponsored by the National Institutes of Health, approximately 40% of 2054 HIV-infected women and 17% of HIV-negative at-risk women were found to have abnormal Pap smears at the time of their initial study visit.[6] Abnormal Pap smears were shown to correlate with HIV infection, CD4+ cell count < 200 cells/mm3, HPV infection, and infection with high-risk HPV types or with multiple types of HPV. The relationship between HIV infection[7-10] and/or lower CD4+ cell count[11] and increased likelihood of CIN is well documented. Higher plasma HIV-1 RNA levels have also been associated with increased risk of CIN.[12]
As might be expected by the high prevalence of abnormal Pap smears, HPV infection is also very common in HIV-infected women, detected in 58% of 2015 HIV-infected women vs 26% of matched, uninfected controls.[13] The prevalence of HPV is even higher in women with CD4+ cell counts < 200 cells/mm3[9] or high HIV-1 viral load.[14] Of importance, HIV-infected women are also more likely to demonstrate persistence of HPV infection over time,[15,16] a factor associated with development of invasive cervical cancer in HIV-negative women.[17] Invasive cervical cancer was added to the list of AIDS-defining conditions in 1993.
Aside from cervical neoplasia, HPV has also been associated with anal precursor lesions and invasive anal carcinoma. Anal intraepithelial neoplasia (AIN) is common among HIV-infected men who have sex with men (MSM).[18,19] Furthermore, before the widespread availability of highly active antiretroviral therapy (HAART), more than 50% of HIV-infected MSM with a CD4+ cell count < 500 cells/mm3 and 33% of those with a CD4+ cell count > 500 cells/mm3 developed AIN 2 or 3 within 4 years of follow-up.[20,21] Although not considered an AIDS-defining lesion, the relative risk of anal cancer among HIV-infected men is approximately 37-fold greater than that expected in the general population, and the relative risk is also increased (6.8-fold) among HIV-infected women.[22]
The ability of HAART to ameliorate known precursor lesions in the anus or cervix or to prevent the development of precursor or invasive disease is currently unclear, and results have been inconsistent. Thus, regression of cervical precursor lesions has been reported in some studies of HIV-infected women treated with HAART,[23,24] while other studies have found no such effect.[25,26] In theory, if HAART is associated with improvements in immune function over time, one might expect that the incidence of genital HPV infection might go down, with resultant decrease in precursor lesions and, eventually, a decrease in the incidence of invasive carcinoma of the cervix or anus. Alternatively, the incidence of these lesions might increase over time, as HIV-infected persons live longer in the setting of imperfect immune reconstitution. During the 6th International Conference on Malignancies in AIDS & Other Immunodeficiencies, Richard Reichman[27] from the University of Rochester, Rochester, New York, provided an overview of current data concerning the effect of HAART on HPV infection and precursor lesions of the cervix and anus in HIV-infected patients.
Reichman reviewed the study by Heard and colleagues[23] that demonstrated a statistically significant decrease in cervical precursor lesions (from 69% to 53%, P = .04) and in colposcopic abnormalities (from 79% to 67%, P = .001) in 49 HIV-infected women after use of HAART for a median of 5 months. Precursor lesions were more likely to regress in those women who experienced increase in CD4+ cell count after initiating HAART. Of interest, however, there was no change in the prevalence of HPV DNA in these women during the same time interval.
Minkoff and colleagues[24] studied 741 women (representing 41.6% of the WIHS cohort) in whom at least 1 high-risk oncogenic HPV subtype was detected during the first 3 study visits, which occurred at 6-month intervals. Pap smears from each participant's consecutive visits were defined as a pair, and were evaluated in terms of either regression or progression of cytologic abnormalities over time. Results were correlated with HPV results and HAART exposure. Women who had persistent HPV infection were more likely to have progression of cytologic abnormalities. After adjusting for CD4+ cell count and status of the Pap smear, women who received HAART were statistically less likely to have progression of cytologic abnormalities, and were 40% more likely to have regression of these abnormalities. This study would indicate that HAART has a beneficial effect on the natural history of HPV disease.
Additional data, however, suggest that HAART may not be beneficial in terms of HPV infection or regression of early precursor lesions. Squires and colleagues[26] from the AIDS Clinical Trials Group (ACTG) performed a substudy (ACTG 866) of ACTG study 320,[28] in which 1156 patients were enrolled in a randomized, placebo-controlled study of zidovudine or stavudine plus lamivudine or both lamivudine and indinavir. Substudy 866 evaluated 95 of the 202 women who had been enrolled in ACTG 320, of whom 51 had been assigned to receive the 3-drug HAART regimen and the remaining 44 received dual therapy. Study visits occurred at baseline, 6 months, and 10 months from initiation of therapy. At baseline, 53% of the women had an abnormal Pap smear. At 6 months, 40% of women had abnormal Pap smears, increasing to 66% at 10 months. There were no significant differences between the 2 treatment groups in terms of Pap smear abnormalities. Furthermore, while genital tract HIV-1 RNA levels decreased over time, there was no correlation between Pap smear results and presence or amount of genital tract HIV-1 RNA.[26]
The Lillo study[25] monitored 163 HIV-infected women, of whom 65% were HPV-positive. A total of 27 patients had untreated HIV infection, 62 were treated with reverse transcriptase inhibitors, and 74 received HAART. The median CD4+ cell counts of these 3 groups were 627, 336, and 260 cells/mm3, respectively. High-risk HPV infections were detected in 68% of the women, while 20.2% had low-grade squamous intraepithelial lesions (SIL) and 6.2% had high-grade SIL at baseline. The risk of HPV infection or SIL both increased with declining CD4+ cell count. After a median follow-up of 15.4 months, there were no differences in terms of persistence of high-risk HPV infection or progression of SIL among treatment groups, indicating that HAART may not have a protective effect in terms of HPV or SIL, at least in the short term.
No study has yet addressed the ultimate effect of HAART on prevention of invasive cervical cancer. Of interest, the International Collaborative Study analyzed data from 11 international cohort studies on AIDS-related malignancies and found no decrease in cervical cancer coincident with the widespread availability of HAART.[29]
Recent data regarding anal precursor lesions and anal cancer in the era of HAART are of concern. Data from the Anal Neoplasia Study in San Francisco, California, indicate that HAART has had no effect on the incidence or progression of AIN.[30] Piketty and colleagues[31] presented data on 46 PI-experienced MSM enrolled in a cross-sectional study. The patients had received antiretrovirals for a mean of 57 months, including PI-based therapy for an average of 31 months. The mean CD4+ cell count at initiation of PI therapy was 123 cells/mm3, increasing to 294 cells/mm3 at the time of study entry. Anal cytologic abnormalities were present in 72% of the patients, with high-grade SIL in 22% and low-grade SIL in 44%. As would be expected, HPV DNA was detected in 80% of the patients, with oncogenic types demonstrated in 59%. Of interest, among those patients with detectable HPV DNA, an average of 2.4 different HPV types were present. The prevalence of anal squamous intraepithelial lesions (ASIL) and HPV in relation to the CD4+ cell count response to therapy are shown in Table 1. The authors concluded that anal HPV disease and HPV itself persist despite prolonged response to antiretroviral therapy.
| Response to Therapy | Prevalence of ASIL | Prevalence of HPV |
|---|---|---|
| CD4+ cell count increase of ≥ 100 cells/mm3 | 82% | 79% |
| CD4+ cell count increase of < 100 cells/mm3 | 77% | 54% |
In an attempt to clarify the effect of HAART use on anal HPV infection, Critchlow and colleagues[32] analyzed outcomes among HIV-infected MSM from the Seattle, Washington, area, comparing the pre-HAART and post-HAART periods. A longitudinal study of 102 HIV-infected men was initiated, all of whom began HAART during the study period. Patients were assessed every 4 months. The mean follow-up period was 3.5 years, including 2.6 years after initiation of HAART. Presence of HPV DNA was assessed by PCR, and anal Pap smears and/or biopsy material were evaluated for cytologic or histologic changes of AIN or invasive cancer. The slope (change) of the CD4 cell count was calculated from the pre-HAART era and was used to estimate what the CD4+ cell count level would have been in the future, had HAART not been used. The findings are summarized in Table 2. As the duration of HAART therapy increased, the prevalence of HPV infection and of low-grade AIN also decreased, suggesting that HAART may eventually be associated with a decrease in the risk of high-grade AIN and/or anal carcinoma. However, at the current time, this study did not confirm a decrease in the risk of high-grade AIN after initiation of HAART.
|
|
Pre-HAART (227 visits) | Post-HAART (767 visits) | Relative Risk | 95% Confidence Interval |
|---|---|---|---|---|
| HPV Detection: | ||||
| Any high-risk HPV | 74% | 60% | 0.43 | 0.27-0.69 |
| HPV 16 | 45% | 35% | 0.57 | 0.38-0.85 |
| HPV 18 | 19% | 12% | 0.59 | 0.36-0.97 |
| Results of Cytology: | ||||
| Low-grade AIN | 58% | 33% | 0.28 | 0.20-0.40 |
| High-grade AIN | 5% | 10% | 1.71 | 0.86-3.41 |
Palefsky and colleagues[33] evaluated the prevalence of high-grade AIN among MSM in the post-HAART era. These investigators have previously found that the vast majority of HIV-infected MSM from the San Francisco area have evidence of anal HPV infection, documented in approximately 75% with CD4+ cell counts > 500 cells/mm3 and approximately 95% of those with CD4+ cell counts < 200 cells/mm3. A cross-sectional study was undertaken, which included 357 HIV-infected and 205 HIV-negative MSM accrued from February 1998 and January 2000 at the University of California, San Francisco. High-resolution anoscopy was performed in all patients and visible lesions were biopsied. The majority of the patients were white (85%), and the median age of the HIV-infected subjects was 42.4 years. Approximately 30% had graduated from college, and the median time since their first HIV-positive blood test was 130 months. The vast majority of patients were taking antiretroviral therapy, and only 7% reported no history of antiretroviral therapy. At study entry, 75% were taking HAART and 86% were taking at least 1 antiretroviral agent. Of importance, 52% of the HIV-infected men had evidence of AIN 2 or 3. On multivariate analysis, factors that were statistically associated with high-grade AIN included evidence of HPV infection, use of any antiretroviral therapy, and use of HAART. Surprisingly, then, HAART use was associated with a statistically increased risk of high-grade AIN in this cohort, even when the data were adjusted for CD4+ cell count. These data are of interest, and evoked a good deal of discussion at the meeting.
The HPV genome is integrated within tumor cell DNA in patients with cervical or anal neoplasia, resulting in the expression of E6 and/or E7 oncoproteins, which serve to downregulate p53 suppressor activity, leading to genomic instability, evolution towards a malignant phenotype, and the eventual development of invasive carcinoma. It is possible that HAART may be effective in reducing reactivation or persistence of HPV infection. This, in turn, could be associated with a decrease in the development of low-grade precursor lesions over time, as described by Critchlow and colleagues.[32] However, if these lesions have already progressed molecularly, it may be impossible for HAART to overcome these molecular events, leading to persistence of high-grade disease with the potential for further evolution to invasive carcinoma. Palefsky plans to study his cohort prospectively; it will be extremely important to decipher the long-term sequelae of high-grade AIN and to ascertain the rate at which these lesions progress to frank invasive carcinoma. Unfortunately, data at this time would indicate that HAART will probably not be associated with a reversal of high-grade anal lesions. In terms of invasive anal carcinoma, data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) cancer registry from the Greater (San Francisco) Bay Area have shown an increased incidence of anal cancer among all men and women aged 40-64 years between 1973 and 1999.[34] While these data are not specific for HIV-infected patients, they indicate that the incidence of anal cancer continues to increase substantially despite the widespread use of HAART among HIV-infected individuals living in the Greater Bay Area.
