This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bower, M. Articles by Stebbing, J. Search for Related Content PubMed PubMed Citation Articles by Bower, M. Articles by Stebbing, J. Social Bookmarking                            What's this?

Should Cervical Cancer Be an Acquired Immunodeficiency Syndrome–Defining Cancer?

Departments of Oncology and HIV Medicine, Chelsea and Westminster Hospital, London, United Kingdom

In 1987, the Centers for Disease Control and Prevention created a list of clinical diagnoses that defined the types of AIDS that were indicative of severe immunosuppression, especially defective cell-mediated immunity. Kaposi's sarcoma (KS) and high-grade non-Hodgkin's lymphoma (NHL) were included in this list of AIDS-defining illnesses. More precisely, KS and primary cerebral NHL in people less than 60 years old were AIDS-defining illnesses even in the absence of HIV serology. In contrast, systemic high-grade B-cell NHL had to have either small noncleaved (Burkitt's and Burkitt's-like) or immunoblastic histology and have positive HIV serology to be an AIDS-defining illness.¹

In 1993, the definition of AIDS was revised chiefly to include all patients with a CD4 cell count less than 200/µL. However, three more AIDS-defining illnesses were added to the list, including invasive cervical cancer.² The addition of invasive cervical cancer was somewhat controversial because, at that time, only an increased incidence of cervical intraepithelial neoplasia had been established in HIV-positive women.^3,4 Although this was thought to be associated with increased immunosuppression, there were no clear data on the incidence of invasive cervical cancer. Part of the reasoning behind the inclusion of invasive cervical cancer as an AIDS diagnosis may have originated in sub-Saharan Africa, where more than half of the people infected by HIV are women with little access to cervical cancer screening.⁵ Moreover, it was thought that the prolonged incubation time of more than 10 years from cervical human papillomavirus (HPV) infection progressing through cervical intraepithelial neoplasia (CIN) to invasive cervical cancer may have accounted for the low incidence of invasive cervical cancer in HIV-seropositive women whose life expectancy in many parts of the world would have been shorter than this time.

When first introduced in 1987, an AIDS-defining illness was a surrogate marker of advanced immunosuppression, and thus, in the current era of highly active antiretroviral therapy (HAART), an AIDS-diagnosing illness should retain this property. Moreover, to be included as an AIDS-defining cancer, the malignancy ought to occur at increased risk in the HIV-positive population, and this risk should increase as the CD4 cell count decreases. Importantly, since the introduction of HAART in established market economies, with its accompanying increase in CD4 cell count, the incidence of the AIDS-defining cancers should have declined. Finally and ideally, the overall survival of an AIDS-defining cancer ought to have improved with the introduction of HAART. Let us apply these criteria to the three current AIDS-defining cancers.

The era of AIDS was heralded in 1981 by the emergence of two previously uncommon diseases, Pneumocystis carinii pneumonia (previously named Pneumocystis jirovecii) and an aggressive form of KS.^6,7 The relative risk of KS in the HIV-positive population has been calculated as many thousands.⁸ Epidemiologic evidence for a reduction in the incidence of AIDS-related KS as a first AIDS diagnosis was confused by the alterations to the definition of AIDS by the US Centers for Disease Control and Prevention, most recently in 1993. However, a declining incidence was already noted in several cohorts in the early 1990s before the introduction of HAART; indeed, the incidence of KS in American men with AIDS decreased from 40% in 1981 to less than 20% in 1992.⁹ This is thought to have reflected a decreasing prevalence of human herpesvirus-8 infection in the HIV-positive population as transmission risk groups changed. A clear relationship between both CD4 cell count and progressive immunosuppression with risk of KS has been demonstrated.^8,10 Nonetheless, KS remains the most common AIDS-associated cancer in the United States and an important cause of morbidity and mortality, particularly in sub-Saharan Africa.^11,12

The introduction of HAART in 1996 was followed by a decrease in incidence of KS both as a first AIDS diagnosis and as a subsequent manifestation in HIV-seropositive cohorts.^8,13 This decline has been shown to be a result of the use of HAART because a large cohort study demonstrated that HAART protects against the development of KS in people with HIV.¹⁴ Furthermore, in patients with established KS, the introduction of HAART therapy is associated with a prolongation of the time to treatment failure of KS¹⁵ and may be used as sole therapy for early-stage KS. Thus, HAART therapy has a major influence both on the epidemiology and clinical progression of KS without apparently having a direct effect on its causative herpesvirus. The postulated mechanism of this effect is the immune reconstitution of cytotoxic T-lymphocyte responses to human herpesvirus-8 and suppression of HIV replication.^16,17 In addition, recent publications have confirmed that HAART is associated with a prolongation of survival after a diagnosis of KS.¹⁸

For high-grade NHL, meta-analysis of cohort studies confirms a decrease in incidence in the era of HAART,⁸ and individual studies confirm that this is a result of the protective effects of HAART.¹⁹ Again, there is a clear relationship between the risk of NHL and the CD4 cell count and also progressive immunosuppression.^8,10 Recently, a number of groups have described an improvement in the overall survival of patients with systemic NHL compared with historical controls since the introduction of HAART. The complete remission rate and overall survival with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy has improved with the addition of HAART to the chemotherapy,^20,21 and the goal of therapy is clearly complete remission and not palliation.²² The improved survival described since the introduction of HAART and the preservation of immune function suggests that the combination of chemotherapy with HAART is an important step forward in the management of AIDS-related lymphomas. However, there are both toxicity and pharmacokinetic drawbacks to the concomitant administration of chemotherapy and HAART. For example, the potentiation of myelotoxicity observed when chemotherapy is combined with protease inhibitors may be a consequence of microsomal enzyme inhibition reducing the metabolism of cytotoxics in the regimen.²³

Thus, the three parameters of increasing risk with decreasing CD4 count, reduction of risk by HAART, and improved survival with HAART are fulfilled for both KS and NHL. This supports the continued status of these herpesvirus-associated malignancies as AIDS-defining cancers in the era of HAART. As far as invasive cervical cancer is concerned, demonstration of a statistically significant increased relative risk in HIV-seropositive women was delayed until this millennium.^24,25 However, earlier, there was good epidemiologic evidence that the precursor lesions, CIN or squamous intraepithelial lesion (SIL), occurred more frequently in women with HIV.²⁶ The relative risk of invasive cervical cancer in both an international meta-analysis of 20 cohorts and the Swiss cohort studies is four- to six-fold compared with approximately 60-fold for NHL and more than 1,000-fold for KS.^24,25 Moreover, these data also demonstrate no clear relationship between the risk of cervical cancer and either CD4 cell count or progression to AIDS. In view of these findings, it is perhaps not surprising that there has been no decline in the incidence of cervical cancer in the era of HAART.⁸ There are no publications that address the overall survival of invasive cervical cancer that compare the pre- and post-HAART eras.

However, the Women's Interagency HIV Study has found an increasing risk of SILs with decreasing CD4 cell count, and this was usually associated with the presence of multiple, often high-risk HPV genotypes.²⁶ The effect of HAART on these preinvasive lesions is controversial. In one study of 49 women with advanced HIV, within 5 months after starting HAART, the prevalence of CIN decreased from 66% to 49%, regression of high-grade SIL to low-grade SIL occurred in 23% of patients, and regression of low-grade SIL to normal occurred in 43% of patients. These changes occurred without a significant change in the level of HPV DNA in cervical tissue.²⁷ Similarly, in a Women's Interagency HIV Study cohort from five US cities, the effect of HAART on CIN was assessed by smear testing every 6 months. After adjustment for CD4 cell count and Papanicolaou smear status, women on HAART were 40% (95% CI, 4% to 81%) more likely to demonstrate regression and less likely (odds ratio = 0.68; 95% CI, 0.52 to 0.88) to demonstrate progression.²⁸ However, the benefits of HAART have not been reproduced in all studies, and HAART seems to have limited ability to clear HPV infection and induce regression of CIN in HIV-positive women. These findings suggest that cervical smears should be offered to all HIV-positive women, although the frequency remains controversial.²⁹

There seems to be little evidence to support the continuing designation of invasive cervical cancer as an AIDS-defining cancer in the era of HAART because it seems not to have a clear strong relationship to immune function as determined by CD4 cell count or responsiveness to HAART. Perhaps for these reasons, we predict that HPV-associated malignancies, including cervical and anal cancers,³⁰ will persist within the HIV population despite HAART and will become an increasing health burden for people living with HIV. The effect of the new HPV vaccines in HIV-positive individuals also remains to be elucidated.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

Author Contributions

Conception and design: Mark Bower, Justin Stebbing Financial support: Justin Stebbing Administrative support: Danish Mazhar, Justin Stebbing Provision of study materials or patients: Mark Bower, Danish Mazhar, Justin Stebbing Collection and assembly of data: Mark Bower, Danish Mazhar, Justin Stebbing Data analysis and interpretation: Mark Bower, Danish Mazhar, Justin Stebbing Manuscript writing: Mark Bower, Danish Mazhar, Justin Stebbing Final approval of manuscript: Mark Bower, Justin Stebbing

 

REFERENCES

1. Centers for Disease Control: Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome: Council of State and Territorial Epidemiologists; AIDS Program, Center for Infectious Diseases. MMWR Morb Mortal Wkly Rep 36:1S-15S, 1987 (suppl 1)

2. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep 41:1-19, 1992[Medline]

3. Laga M, Icenogle JP, Marsella R, et al: Genital papillomavirus infection and cervical dysplasia: Opportunistic complications of HIV infection. Int J Cancer 50:45-48, 1992[Medline]

4. Schafer A, Friedmann W, Mielke M, et al: The increased frequency of cervical dysplasia-neoplasia in women infected with the human immunodeficiency virus is related to the degree of immunosuppression. Am J Obstet Gynecol 164:593-599, 1991[Medline]

5. Wabinga H, Ramanakumar AV, Banura C, et al: Survival of cervix cancer patients in Kampala, Uganda: 1995-1997. Br J Cancer 89:65-69, 2003[Medline]

6. Centers for Disease Control: Kaposi's sarcoma and Pneumocystis pneumonia among homosexual men: New York City and California. MMWR Morb Mortal Wkly Rep 30:305-308, 1981[Medline]

7. Friedman-Kien A, Laubenstein L, Marmor M, et al: Kaposi's sarcoma and pneumocystis pneumonia among homosexual men: New York and California. MMWR Morb Mortal Wkly Rep 30:250-254, 1981[Medline]

8. International Collaboration on HIV and Cancer: Highly active antiretroviral therapy and incidence of cancer in human immunodeficiency virus-infected adults. J Natl Cancer Inst 92:1823-1830, 2000[Abstract/Free Full Text]

9. Jacobson L: Impact of highly effective anti-retroviral therapy on the incidence of malignancies among HIV infected individuals. J AIDS Hum Retrovirol 9:A39, 1998

10. Frisch M, Biggar RJ, Engels EA, et al: Association of cancer with AIDS-related immunosuppression in adults. JAMA 285:1736-1745, 2001[Abstract/Free Full Text]

11. Gondos A, Brenner H, Wabinga H, et al: Cancer survival in Kampala, Uganda. Br J Cancer 92:1808-1812, 2005[Medline]

12. Mbulaiteye SM, Katabira ET, Wabinga H, et al: Spectrum of cancers among HIV-infected persons in Africa: The Uganda AIDS-Cancer Registry Match Study. Int J Cancer 118:985-990, 2006[CrossRef][Medline]

13. Jacobson LP, Yamashita TE, Detels R, et al: Impact of potent antiretroviral therapy on the incidence of Kaposi's sarcoma and non-Hodgkin's lymphomas among HIV-1-infected individuals: Multicenter AIDS Cohort Study. J Acquir Immune Defic Syndr 21:34-41, 1999

14. Portsmouth S, Stebbing J, Gill J, et al: A comparison of regimens based on non-nucleoside reverse transcriptase inhibitors or protease inhibitors in preventing Kaposi's sarcoma. AIDS 17:F17-F22, 2003[CrossRef][Medline]

15. Bower M, Fox P, Fife K, et al: Highly active anti-retroviral therapy (HAART) prolongs time to treatment failure in Kaposi's sarcoma. AIDS 13:2105-2111, 1999[CrossRef][Medline]

16. Stebbing J, Bourboulia D, Johnson M, et al: Kaposi's sarcoma-associated herpesvirus cytotoxic T lymphocytes recognize and target Darwinian positively selected autologous K1 epitopes. J Virol 77:4306-4314, 2003[Abstract/Free Full Text]

17. Osman M, Kubo T, Gill J, et al: Identification of human herpesvirus 8-specific cytotoxic T-cell responses. J Virol 73:6136-6140, 1999[Abstract/Free Full Text]

18. Gallafent JH, Buskin SE, De Turk PB, et al: Profile of patients with Kaposi's sarcoma in the era of highly active antiretroviral therapy. J Clin Oncol 23:1253-1260, 2005[Abstract/Free Full Text]

19. Stebbing J, Gazzard B, Mandalia S, et al: Antiretroviral treatment regimens and immune parameters in the prevention of systemic AIDS-related non-Hodgkin's lymphoma. J Clin Oncol 22:2177-2183, 2004[Abstract/Free Full Text]

20. Navarro JT, Ribera JM, Oriol A, et al: Influence of highly active anti-retroviral therapy on response to treatment and survival in patients with acquired immunodeficiency syndrome-related non-Hodgkin's lymphoma treated with cyclophosphamide, hydroxydoxorubicin, vincristine and prednisone. Br J Haematol 112:909-915, 2001[CrossRef][Medline]

21. Spina M, Jaeger U, Sparano JA, et al: Rituximab plus infusional cyclophosphamide, doxorubicin, and etoposide in HIV-associated non-Hodgkin lymphoma: Pooled results from 3 phase 2 trials. Blood 105:1891-1897, 2005[Abstract/Free Full Text]

22. Spina M, Carbone A, Vaccher E, et al: Outcome in patients with non-hodgkin lymphoma and with or without human immunodeficiency virus infection. Clin Infect Dis 38:142-144, 2004[CrossRef][Medline]

23. Bower M, McCall-Peat N, Ryan N, et al: Protease inhibitors potentiate chemotherapy-induced neutropenia. Blood 104:2943-2946, 2004[Abstract/Free Full Text]

24. Frisch M, Biggar RJ, Goedert JJ: Human papillomavirus-associated cancers in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. J Natl Cancer Inst 92:1500-1510, 2000[Abstract/Free Full Text]

25. Clifford GM, Polesel J, Rickenbach M, et al: Cancer risk in the Swiss HIV Cohort Study: Associations with immunodeficiency, smoking, and highly active antiretroviral therapy. J Natl Cancer Inst 97:425-432, 2005[Abstract/Free Full Text]

26. Palefsky JM, Minkoff H, Kalish LA, et al: Cervicovaginal human papillomavirus infection in human immunodeficiency virus-1 (HIV)-positive and high-risk HIV-negative women. J Natl Cancer Inst 91:226-236, 1999[Abstract/Free Full Text]

27. Heard I, Schmitz V, Costagliola D, et al: Early regression of cervical lesions in HIV-seropositive women receiving highly active antiretroviral therapy. AIDS 12:1459-1464, 1998[CrossRef][Medline]

28. Minkoff H, Ahdieh L, Massad LS, et al: The effect of highly active antiretroviral therapy on cervical cytologic changes associated with oncogenic HPV among HIV-infected women. AIDS 15:2157-2164, 2001[CrossRef][Medline]

29. Harris TG, Burk RD, Palefsky JM, et al: Incidence of cervical squamous intraepithelial lesions associated with HIV serostatus, CD4 cell counts, and human papillomavirus test results. JAMA 293:1471-1476, 2005[Abstract/Free Full Text]

30. Bower M, Powles T, Newsom-Davis T, et al: HIV-associated anal cancer: Has highly active antiretroviral therapy reduced the incidence or improved the outcome? J Acquir Immune Defic Syndr 37:1563-1565, 2004[Medline]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				J.-P. Spano, D. Costagliola, C. Katlama, N. Mounier, E. Oksenhendler, and D. Khayat AIDS-Related Malignancies: State of the Art and Therapeutic Challenges J. Clin. Oncol., October 10, 2008; 26(29): 4834 - 4842. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bower, M. Articles by Stebbing, J. Search for Related Content PubMed PubMed Citation Articles by Bower, M. Articles by Stebbing, J. Social Bookmarking                            What's this?