Long-term effect of highly active antiretroviral therapy on cervical lesions in HIV-positive women
Uberti-Foppa, Caterinaa; Ferrari, Davideb; Lodini, Sarad; Reina, Salvatoree; Ameglio, Francof; Grasso, Maria Angelad; Gallotta, Giuliaa; Ferrari, Augustob; Taccagni, Gianlucac; Lazzarin, Adrianoa; Lillo, Flavia Bd
Departments of aInfectious Diseases, bObstetrics and Gynecology, and cPathology, and dLaboratory of Virology, IRCCS San Raffaele Hospital, Milan, Italy; eCso Solferino 5, Genova, Italy; and fLaboratory of Clinical Pathology, S. Giovanni di Dio Hospital, FBF/AFAR, Rome, Italy.
Sponsorship: This work was partly supported by the Italian Ministry of Health funds 2000 (convention RF00.55).
Received: 14 November 2002; revised: 3 April 2003; accepted: 7 May 2003.
This prospective study evaluated the effect of long-term highly active antiretroviral therapy (HAART) on human papillomavirus-related cervical disease in clinically stable HIV-positive women on unchanged therapy and those switching to HAART because of virological worsening. Only the clinically stable (P = 0.00004) and HAART-treated women in the same group (P = 0.0009) showed a reduction in lesions, thus suggesting that strict preventative regimens for invasive lesions are also needed in the HAART era.
HIV-seropositive patients represent the largest population with persistent anogenital human papillomavirus (HPV) infection (40–60% of most series). A low CD4 cell count and high HIV-RNA viraemia levels are definite risk factors for harbouring oncogenic HPV types [1–7]. The introduction of highly active antiretroviral therapy (HAART) has greatly reduced the morbidity and mortality of HIV-infected patients, but its effect on anogenital cancers is still unclear [8–11].
As the persistence of high-risk HPV in the general population also represents a highly significant risk for the subsequent development of cervical cancer, we prospectively followed 154 HIV-positive women at intervals of 6–12 months and recorded their immunological (CD4 cell counts), virological (HIV RNA, HPV DNA) and gynaecological parameters for 36.4 ± 10.4 months.
In order to assess the long-term effects of HAART on the development of HPV-related cervical diseases, we divided our patients into those with stable clinical, immunological and virological pictures who were untreated or did not change their ongoing therapy (group S: n = 83) and those who switched to more potent HAART because of HIV-RNA relapse after effective antiretroviral therapy (group W: n = 71). At baseline, 41 women were in CDC stage A, 80 in stage B, and 33 in stage C; there was a borderline significant between-group difference in patient distribution only for stage B (S = 30 versus W = 50; P = 0.05).
The mean age of the patients was 32.3 ± 5.2 years (range 21–45); the main HIV risk factors were heterosexual intercourse (54.2%) and drug abuse (44%).
The women were defined as being persistently, sporadically or non-HPV infected, respectively, when the same HPV types were detected always, once or twice during follow-up, or never using Hybrid Capture II (Digene Corp., Beltville, MD, USA) or genomic amplification followed by specific hybridization with oligomeric probes (MY09–MY11 and SPF10 primers) [12,13].
PAP smears and histological lesions were classified according to the recently modified Bethesda system . Significance and sample variability were calculated using parametric or non-parametric statistics (as necessary) and EPI-Info 2000 (Centers for Disease Control and Prevention, Atlanta, GA, USA), World Health Organization Global Programme (Geneva, Switzerland) or StatGraphics 2.6 software (STSC, Rockville, MD, USA).
Table 1 shows the baseline and endpoint characteristics of the HIV-positive women with or without HPV-related cervical lesions receiving different antiretroviral therapies or no treatment.
The women with high-grade squamous intraepithelial lesions (HgSIL) had lower mean CD4 cell counts (303 ± 220 versus 415 ± 269; P = 0.053) and more advanced HIV disease, with a global prevalence of 8.3% in stage C, 4.2% in stage B, and 3% in stage A (trend test P = 0.095).
HgSIL were only reported in women with detectable high-risk HPV, and increased with the number of oncogenic HPV-positive samples (0% in those with no or only one high-risk HPV detection, 7.9% in those with two positive readings, and 21.3% in those with three positive readings; P = 0.009), being significantly more frequent (P = 0.003) in women infected with high-risk HPV at enrolment. CD4 cell counts were 386 ± 191 cells/μl in women who were persistently HPV negative and 285 ± 212 in those with persistent infection, thus confirming the greater frequency and persistence of oncogenic HPV in more immunocompromised women (P = 0.057).
There was no difference in the CD4 cell counts of the patients with or without HgSIL in group S (P = 0.58), but they were significantly lower in patients with HgSIL in group W (P = 0.045).
HAART treatment significantly increased CD4 cell counts in group S (P = 0.017) and group W (P = 0.001), but this immunoreconstitution was not associated with a decrease in the persistence of high-risk HPV in either group.
As expected, HIV viraemia significantly decreased in patients switching to more potent therapy (P = 0.016), and remained substantially unchanged in those with a stable clinical picture (P = 0.54).
Time-based data analyses (not shown) found no relationship between the type of anti-HIV treatment (no treatment, reverse transcriptase inhibitors or HAART) and PAP smears; none of the treatments were associated with a changed cytological diagnosis, but there was a significant reduction in the number of squamous intraepithelial lesion-positive biopsies in group S women (Table 1, P = 0.00004), especially in those receiving HAART (P= 0.0009), data not shown. Confirmed HgSIL were surgically excised in 13 of the patients in group S (15.6%) and in 19 of those who switched to HAART from a less potent therapy (26.8%). The relatively small number of positive cases and the surgical resection of all of the diagnosed HgSIL prevented any statistical evaluation of the prevalence of histological HgSIL in the two groups.
The everyday management of HIV-positive patients frequently involves unstable situations caused by the evolving clinical picture, drug toxicity, poor therapeutic compliance, and the emergence of drug-resistant HIV strains. These generally lead to therapeutic adjustments based on individual clinical or virological needs, which is why we divided our patients into those with a sufficiently balanced immune status and those with a worsening immune response. As shown in Table 1, CD4 cell class distribution was significantly different at baseline (P = 0.01), but not at the endpoint (P = 0.14) as a result of the effect of antiretroviral therapy.
The progression from HgSIL to invasive neoplasias may require years, and the longer life expectancy of HIV patients receiving HAART may expose them to more frequent cancers; however, unlike in the case of preneoplastic lesions, the long natural history of HPV-related cervical cancer may account for the still relatively small increase in the number of diagnoses.
Since its use as a defining AIDS illness, invasive cervical carcinoma (ICC) has become the most common malignancy among women with AIDS in Europe and the USA [15,16], whereas no increase in the relative risk of ICC has been recorded in Africa and Australia, where HAART is less frequently used .
No reliable data are yet available concerning the incidence of cervical cancer in women on HAART, but an Italian National Institute of Health epidemiological survey did not reveal any reduction in the number of cases between the pre (1994–1995) and post-HAART (2000–2001) eras; they accounted for 0.4 and 0.5% of all AIDS-defining events, respectively . However, our findings show that cervical HPV infection and related diseases persist in many women initiating more potent HAART, whereas longer (36-month) and stable HAART had a beneficial effect. Continuous monitoring of the major determinants of invasive cervical cancer is needed in order to identify the long-term consequences of HAART, because if it has no effect on ICC, a larger number of cases can be expected as a result of the longer survival of immunodepressed individuals.
1. Palefsky JM, Minkoff H, Kalish LA, Levine A, Sacks HS, Garcia P, et al
. Cervicovaginal human papillomavirus infection in human immunodeficiency virus-1 (HIV)-positive and high-risk HIV-negative women. J Natl Cancer Inst
2. Luque AE, Demeter LM, Reichman RC. Association of human papillomavirus infection and disease with magnitude of human immunodeficiency virus (HIV-1) RNA plasma level among women with HIV-1 infection. J Infect Dis
3. Minkoff H, Feldman J, deHovitz J, Landesman S, Burk R. A longitudinal study of human papillomavirus carriage in human immunodeficiency virus-infected and human immunodeficiency virus-uninfected women. Am J Obstet Gynecol
4. Uberti-Foppa C, Origoni M, Maillard M, Ferrari D, Ciuffreda D, Mastrorilli E, et al
. Evaluation of the detection of human papillomavirus genotypes in cervical specimens by hybrid capture screening for precancerous lesions in HIV-positive women. J Med Virol
5. Ellerbrock TV, Chiasson MA, Bush TJ, Sun XW, Sawo D, Brudney K, Wright TC Jr. Incidence of cervical squamous intra-epithelial lesions in HIV-infected women. JAMA
6. Sun XW, Kuhn L, Ellerbrock TV, Chiasson MA, Bush TJ, Wright TC. Human Papilloma-virus infection in women infected with the human immunodeficiency virus. N Engl J Med
7. Palefsky JM, Holly EA, Ralston ML, Jay N. Prevalence and risk factors for human Papillomavirus infection of the anus in human immunodeficiency virus (HIV)-positive and HIV-negative homosexual men. J Infect Dis
8. Minkoff H, Ahdieh L, Massad LS, Anastos K, Watts DH, Melnick S, et al
. The effect of highly active antiretroviral therapy on cervical cytologic changes associated with oncogenic HPV among HIV-infected women. AIDS
9. Heard I, Tassie J-M, Kazatchkine MD, Orth G. Highly active antiretroviral therapy enhances regression of cervical intraepithelial neoplasia in HIV-seropositive women. AIDS
10. Lillo FB, Ferrari D, Veglia F, Origoni M, Grasso MA, Lodini S, et al
. Human papillomavirus infection and associated cervical disease in human immunodeficiency virus-infected women: effect of highly active antiretroviral therapy. J Infect Dis
11. Palefsky JM, Holly EA, Ralston ML, Da Costa M, Bonner H, Jay N, et al
. Effect of highly active antiretroviral therapy on the natural history of anal squamous intraepithelial lesions and anal human papillomavirus infection. J Acquir Immune Defic Syndr
12. Manos MM, Ting Y, Wright DK, Lewis AJ, Broker TR, Wolinsky SM. Use of polymerase chain reaction amplification for the detection of genital human papillomaviruses. Cancer Cells
13. Kleter B, van Doorn LJ, ter Schegget L, Schrauwen L, van Krimpen K, Burger M, et al
. A novel short fragment PCR assay for highly sensitive broad-spectrum detection of anogenital human papillomavirus. Am J Pathol
14. Wright TC, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ. 2001 Consensus guidelines for the management of women with cervical cytological abnormalities. JAMA
15. Gates AE, Kaplan LD. AIDS malignancies in the era of highly active antiretroviral therapy. Oncology
16. Del Mistro A, Chieco Bianchi L. HPV-related neoplasia in HIV-infected individuals. Eur J Cancer
17. Serraino D. The spectrum of AIDS-associated cancers in Africa. AIDS
18. Notiziario Istituto Superiore di Sanità. Aggiornamento dei casi di AIDS notificati in Italia al 31 dicembre 2001
. Rome, Italy: Notiziario Istituto Superiore di Sanità; 2002. p. 15.
© 2003 Lippincott Williams & Wilkins, Inc.