Highly active antiretroviral therapy and cervical dysplasia in HIV-positive women in South Africa

Abstract

Background

The risk of squamous intra-epithelial lesions (SIL) is higher in HIV-positive women. As these women begin to live longer due to highly active antiretroviral therapy (HAART), their risk of cervical cancer may increase. Few data exist regarding the effect of HAART on the incidence and progression of SIL in HIV-positive African women. The aim of this study was to evaluate the effect of HAART on the incidence and progression of SIL in HIV-positive women in South Africa.

Methods

A prospective observational study of HIV-seropositive women was conducted over 5 years in an HIV treatment clinic in Johannesburg, South Africa. The participants consisted of 601 women on and off HAART who had repeat Pap smears greater than 6 months apart. The effect of HAART use on incidence and progression rates of SIL was determined using multivariate Poisson regression to obtain incidence rate ratios (IRRs), adjusted for age, CD4 count and other potential confounders.

Results

Median follow-up time was 445 days (inter-quartile range 383, 671). The crude rate of incidence of any SIL was 15.9 episodes (95% confidence limit (CL) 12.7, 19.9) per 100 person-years; the crude rate of all progression of cervical dysplasia among women was 13.5 episodes (95% CL 11.3, 16.1) per 100 person-years. HAART use was associated with a robust reduction in the rate of incidence and progression of cervical lesions, adjusted IRR=0.55 (95% CL 0.37, 0.80). Sensitivity analyses confirmed this main association held for incidence and progression when they were considered separately, and that the result was not dependent on the length of HAART exposure.

Conclusion

HAART use was associated with a reduction in the rate of both incidence and progression of cervical lesions among HIV-positive women.

References Firnhaber C, Van Le H, Pettifor A, Schulze D, Michelow P, Sanne I, et al. Association between cervical dysplasia and human papillomavirus in HIV seropositive women from Johannesburg South Africa. Cancer Causes Control. 2010;21:433–43. Parham GP, Sahasrabuddhe VV, Mwanahamuntu MH, Shepherd BE, Hicks ML, Stringer EM. Prevalence and predictors of squamous intraepithelial lesions of the cervix in HIV-infected women in Lusaka, Zambia. Gynecol Oncol. 2006;103:1017–102. International Agency for Research Cancer (IARC). GLOBOCAN 2008 cancer fact sheet. Geneva: IARC, 2008. [cited 15 Sept 2010]. Available from: http://globocan.iarc.fr/factsheets/cancers/cervix.asp. Bosch FX, Lorincz A, Munoz N, Meijer CJ, Shah KV. The causal relation between human papillomavirus and cervical cancer. J Clin Pathol. 2002;55: 244–65. Firnhaber CS, Zungu K, Levin S, Michelow P, Michelow P, Montaner LJ, et al. A high prevalence of high risk human papillomavirus and cervical dysplasia in HIV seropositive women in an urban South African Cervical Cancer Cohort (SACCC). Cytologica Acta. 2009;53:10–8. Moscicki AB, Ellenberg JH, Farhat S, Xu J. Persistence of human papillomavirus infection in HIV-infected and -uninfected adolescent girls: risk factors and differences, by phylogenetic type. J Infect Dis. 2004;190:37–45. 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. 1998;178:982–6. El-Sadr WM, Hoos D. The President's Emergency Plan for AIDS Relief – is the emergency over? N Engl J Med. 2008;359:553–5. Nasti G, Martellotta F, Berretta M, Mena M, Fasan M, Di Perri G. Impact of highly active antiretroviral therapy on the presenting features and outcome of patients with acquired immunodeficiency syndrome-related Kaposi sarcoma. Cancer. 2003;11:2440–6. Detels R, Munoz R, McFarlane G, Kingsley LA, Margolick JB, Giorgi J, et al. Effectiveness of potent antiretroviral therapy on time to AIDS and death in men with known HIV infection duration. Multicenter AIDS Cohort Study Investigators. JAMA. 1998;280:1497–503. Heard I, Schmitz V, Costagliola D, Orth G, Kazatchkine MD. Early regression of cervical lesions in HIV-seropositive women receiving highly active antiretroviral therapy. AIDS. 1998;12:1459–64. Minkoff H, Ahdieh L, Massad LS, Anastos K, Watts HD, Melnick S, et al. The effect of highly active antiretroviral therapy on cervical cytologic changes associated with oncogenic HPV among HIV-infected women. AIDS. 2001;15:2157–64. 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. 2001;184:547–51. Ellerbrock TV, Chiasson MA, Bush TJ, Sun XW, Sawo D, Brudney K, et al. Incidence of cervical squamous intraepithelial lesions in HIV-infected women. JAMA. 2000;283:1031–7. Solomon D, Davey D, Kurman R, Moriarty A, O'Connor D, Prey M, et al. The 2001 Bethesda system terminology for reporting results of cervical cytology. JAMA. 2002;287:2114–9. Michelow P, Hartman I, Schulze D, Lamla-Hillie S, Williams S, Levin S, et al. Atypical squamous cells, cannot exclude high grade squamous intraepithelial (ASC-H) in HIV-positive women. Cyto J. 2010;7:1–6. Tshabalala-Msimang ME, Mbewu A, Simelela N, Makubalo L, Hela M, Matsoso P. Operational plan for comprehensive HIV and AIDS care, management and treatment for South Africa. Pretoria: Department of Health; 2003. Massad LS, Evan CT, Minkoff H, Watts DH, Strickler HD, Darragh T, et al. Natural history of grade 1 cervical intraepithelial neoplasia in women with human immunodeficiency virus. Obstet Gynecol. 2004;104:1077–85. Delmas MC, Larsen C, Van Benthem B, Hamers FF, Bergeron C, Poveda JD, et al. Comparative prevalence, incidence and short-term prognosis of cervical squamous intraepithelial lesions amongst HIV-positive and HIV-negative women. AIDS. 2000;14:1775–84. Six C, Heard I, Bergeron C, Ort G, Poveda JD, Zagury P, et al. Comparative prevalence, incidence and short-term prognosis of cervical squamous intraepithelial lesions amongst HIV-positive and HIV-negative women. AIDS. 1998;12: 1047–56. Sanne IM, Westreich D, MacPhail AP, Rubel D, Majuba P, van Rie A. Long-term outcomes of antiretroviral therapy in a large HIV/AIDS care clinic in urban South Africa: a prospective cohort study J Int AIDS Soc. 2009;12:38. doi:10.1186/1758-2652-12–38. Papathakis PC, Rollins NC, Chantry CJ, Bennish ML, Brown KH. Micronutrient status during lactation in HIV infected and HIV uninfected South African women during the first 6 months after delivery. Am J Clin Nutr. 2007;85:182–92. Tomita LY, Longatto F, Costa MC, Andreoli MA, Villa LL, Fraco EL, et al. Diet and serum micronutrients in relation to cervical neoplasia and cancer among low-income Brazilian women. Int J Cancer. 2010;126:703–14. Piyathilake CJ, Macaluso M, Alvarez RD, Bell WC, Heimburger DC, Partridge EE. Lower risk of cervical intraepithelial neoplasia in women with high plasma folate and sufficient vitamin B12 in the post-folic acid fortification era. Cancer Prev Res. 2009;7:658–64. Flately JE, McNeir K, Balasubramani L, Tidy J, Stuart EL, Yong TA, et al. Folate status and aberrant DNA methylation are associated with HPV infection and cervical pathogenesis. Cancer Epidemiol Biomarkers Prev. 2009;18: 2782–9. 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. 2001;184:547–51. Paramsothy P, Jamieson J, Heilig C, Schuman P, Klein R, Schuman P, et al. The effect of highly active antiretroviral therapy on human papillomavirus clearance and cervical cancer. Obstet Gynecol. 2009;113:26–31. Minkoff H, Zhong Y, Burk R, Schuman P, Klein R, Schuman P, et al. Influence of adherent and effective antiretroviral therapy use on human papillomavirus infection and squamous intraepithelial lesions in human immunodeficiency virus-positive women. J Infect Dis. 2010;201:681–90. Soncini E, Zoncada A, Condemi V, Antoni A, Bocchialini E, Soregotti P. Reduction of the risk of cervical intraepithelial neoplasia in HIV-infected women treated with highly active antiretroviral therapy. Acta Biomed. 2007; 78:36–40. Omar T, Schwartz S, Hanrahan C, Modisenyane T, Tshabangu N, Golub J, et al. Progression and regression of premalignant cervical lesions in HIV-infected women from Soweto: a prospective cohort. AIDS. 2011;25:87–93. Sirera G, Videla S, Lopez-Blazquez R, Llatjos M, Tarrats A, Castella E, et al. Evolution of cervical cytologic changes among HIV-infected women with normal cytology in the HAART era. AIDS Res Hum Retroviruses. 2007;23: 965–71. Sirera G, Videla S, Lopez-Blazquez R, Llatjos M, Tarrats A, Castella E, et al. Highly active antiretroviral therapy and incidence of cervical squamous intraepithelial lesions among HIV-infected women with normal cytology and CD4 counts above 350 cells/mm³. J Antimicrob Chemother. 2008;61:191–4. Brennan A, Maskew M, Sanne I, Fox M. The importance of clinic attendance in the first six months on antiretroviral treatment: a retrospective analysis at a large public sector HIV clinic in South Africa. J Int AIDS Soc. 2010;13:49. Kelley CF, Kitchen CM, Hunt PW, Rodriques B, Hecht FM, Kitahata M, et al. Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment. Clin Infect Dis. 2009;48:787–94. Robbins GK, Spritzler JG, Chan ES, Asmuth DM, Gandhi RT, Rodriques BA, et al. Incomplete reconstitution of T cell subsets on combination antiretroviral therapy in the AIDS Clinical Trials Group protocol 384. Clin Infect Dis. 2009; 48:350–61. Lawn SD, Harries AD, William BG, Chaisson RE, Losina E, De Cock KM, et al. Antiretroviral therapy and the control of HIV-associated tuberculosis. Will ART do it? Int J Tuberc Lung Dis. 2011;15:571–81. Lawn SD, Wood R, De Cock KM, Kranzer K, Lewis JJ, Churchyard GJ. Antiretroviral and isoniazid preventive therapy in the prevention of the HIV-associated tuberculosis in settings with limited health-care resources. Lancet Infect Dis. 2010;10:489–98. World Health Organization. Revised ART guidelines. Geneva, Switzerland: 2010 [cited 9 Feb 2011]. Available from: http://whqlibdoc.who.int/publications/2010/9789241599764_eng.pdf