How HIV Affects Cervical Cancer Risk and Outcomes

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The disparity in cervical cancer incidence in women with HIV vs women without HIV is greatest in low and middle-income countries. <i>Photo Credit: James Cavallini/Science Source.</i>
The disparity in cervical cancer incidence in women with HIV vs women without HIV is greatest in low and middle-income countries. Photo Credit: James Cavallini/Science Source.

The prevalence of HIV in women has increased sharply since the early 1980s, when the disease first entered public consciousness.1 Today an estimated 18 million women are living with HIV, representing more than half of HIV-positive adults worldwide.1 In the United States, 25% of HIV-positive individuals are women.1

Early research suggested HIV-positive women had a lower risk for cervical cancer than HIV-negative women.2 Multiple studies, however, have since confirmed that HIV-positive women are significantly more likely to develop cervical cancer.2-4 Most cases of invasive cervical cancer, almost all of which are caused by the human papillomavirus (HPV), are preventable. Scott Dryden-Peterson, MD, an assistant professor at Harvard Medical School and a research associate with the Botswana-Harvard AIDS Institute in Boston, Massachusetts, said, “Improved access to high-functioning HPV testing and other cervical cancer screening modalities would substantially decrease the burden of cervical cancer for women living with and without HIV.” He also predicted that continued expansion of HPV vaccination would significantly reduce the incidence of cervical cancer in the next generation of women.

The relationship between HPV infection and cervical cancer is well established.

Dr Dryden-Peterson said it is less clear, however, why women with HIV have a greater risk of cervical cancer than the general population. The disparity in cervical cancer incidence between women with HIV and women without HIV is greatest in low and middle-income countries (LMICs).2 For example, in Africa, where cervical cancer is the leading cause of cancer death, HIV-infected women are 6 times more likely than uninfected women to develop cervical cancer.3 “The prevailing hypothesis is that HIV-mediated immune dysfunction leads to longer and more intense cervical HPV infections. These infections then lead to oncogenic transformations that lead to cancer,” he said. Supporting this hypothesis, a US study of 334 adolescents age 13 to 18  found it took HIV-negative teens approximately 403 days to clear an initial HPV infection compared with 689 days for HIV-positive teens (P <.0001).5

Persistent high-risk HPV infection promotes the development of cervical intraepithelial neoplasia (CIN), which are precursor lesions for cervical cancer.6 Clearance of the HPV infection frequently leads to regression of low-grade CIN 1/2 lesions.6 Higher-grade CIN2+ lesions may occur if the HPV infection persists for approximately 3 years, and these lesions are more likely to transform into cervical cancer.6 “Earlier initiation of antiretroviral therapy [ART] does appear to reduce the risk of these intense HPV infections and, hopefully, the risk of cervical cancer,” Dr Dryden-Peterson said.

Kelly and colleagues recently reported findings from a meta-analysis of 31 studies (N=6537) that evaluated the relationship between ART initiation, high-risk HPV, and HPV-related cervical lesions.7 They found HIV-positive women using ART had a lower prevalence of high-risk HPV infection than women who were not using ART (odds ratio [OR], 0.83; 95% CI, 0.70-0.99).7 Analyses of the 17 studies that assessed the effect of ART on lesion progression associated ART use with a reduced risk for squamous intraepithelial lesion (SIL) progression (hazard ratio [HR], 0.64; 95% CI, 0.54-0.75), an increased likelihood of SIL or CIN regression (HR, 1.4; 95% CI, 1.30-1.82), and a reduced risk of invasive cervical cancer (HR, 0.40; 95% CI, 0.18-0.87).7 The findings were adjusted for CD4 cell count and treatment duration.

Although studies have associated the introduction of ART with reduced incidence of common AIDS-emergent cancers such as Kaposi sarcoma and non-Hodgkin lymphoma, they have not found a similar reduction in the incidence of cervical cancer.2,3 Per the meta-analysis by Kelly, et al, women who had higher nadir CD4 cell counts derived the greatest benefit regarding cervical cancer risk from ART use. Compared with women who had low nadir CD4 cell counts, women with higher counts had a 36% to 70% reduction in the risk for high-risk HPV and a 36% to 80% reduction in the risk for CIN2+.7 Many women with HIV do not start ART until their nadir CD4 cell counts are low and their HIV viral load is high. In addition, ART does not restore HIV-depleted mucosal CD4+ cells, which are suspected of potentiating HPV infection and progression.3,8 According to Kelly and associates, earlier initiation of ART and better adherence may decrease the risk of HPV infection and progression to cervical cancer.7

Dr Dryden-Peterson said early detection of HIV infection could also reduce the risk of cervical cancer. In addition to facilitating earlier use of ART, prompt diagnosis of HIV would allow routine screening for HPV infection in HIV-positive women. The US guidelines for preventing opportunistic infections in individuals with HIV provide detailed recommendations on how and when to screen females for cervical cancer.9 The US guidelines also recommend HPV vaccination in HIV-infected males and females age 9 through 26, ideally before exposure to HPV.8

In LMICs, access to cervical cancer screening and HPV vaccines may be limited by financial constraints. As a result, most cases of cervical cancer in LMICs are diagnosed at a locally advanced stage.2 The standard treatment for locally diagnosed cervical cancer includes chemoradiation. “Most women living with HIV do not have access to needed radiation therapy and thus have no effective treatment options,” Dr Dryden-Peterson said. He explained that many countries in Africa do not have any radiation facilities and the ones that do have limited capacity. “Expansion of the number of radiation units would improve survival [of HIV-positive women with cervical cancer],” he said. He noted that HIV also affects mortality risk in US women with cervical cancer in part because “providers in the US seem to be less willing to provide curative therapy to women with HIV infection.”

Dr Dryden-Peterson said the effect of HIV on cervical cancer mortality in women receiving appropriate therapy for HIV and cancer is unclear. Between 2010 and 2015, he and his colleagues conducted a prospective study in 348 women from Botswana who had cervical cancer,3 two-thirds of whom (n=231) were HIV-positive. Despite use of ART and guideline-concordant chemoradiation, HIV nearly doubled the risk for cervical cancer mortality (HR, 1.95; 95% CI, 1.20-3.17).3 Many women in the study did not complete or interrupted treatment, which likely contributed to the poor survival outcomes. Dr Dryden-Peterson said many hypotheses have been proposed for why HIV increases mortality risk despite use of appropriate treatments, including “decreased efficacy of cellular immune responses to preserve oncologic remission, decreased tolerance of the chemotherapy and radiation used to treat, and increased prevalence of anemia in HIV infected women, which impairs efficacy of radiation.”

The best strategy for reducing cervical cancer mortality in HIV-infected women is to prevent them from contracting HPV. For women younger than 27, HPV vaccination is a critical component of prevention.4 However, many women are older at the time of HIV diagnosis and others already have HPV or cervical cancer. Dr Dryden-Peterson said for these women survival depends on expanding programs to facilitate prompt diagnosis and to engage patients with cervical cancer in oncology care.

Summary and Clinical Applicability

Women with HIV have an increased risk for persistent HPV infection, which frequently progresses to cervical cancer. The burden of HPV in HIV-positive women is especially high in LMICs. Women with HIV should be warned of their increased risk for HPV and cervical cancer and, when appropriate, advised to undergo HPV vaccination. They should also be routinely screened for HPV, starting at the time of HIV diagnosis. Evidence suggests the introduction of ART before low nadir CD4 counts may improve outcomes in women with concurrent HIV and HVP. Programs that facilitate early detection of cervical cancer and promote guideline-concordant treatment should be expanded in the United States and in LMICs.

References

  1. AMFAR website. Statistics: women and HIV/AIDS. Updated August 2017. Accessed November 10, 2017.
  2. Ghebre RG, Grover S, Xu MJ, Chaung LT, Simonds H. Cervical cancer control in HIV-infected women: past, present and future. Gynecol Oncol Rep. 2017;21:101-108.
  3. Dryden-Peterson S, Bvochora-Nsingo M, Suneja G, et al. HIV infection and survival among women with cervical cancer. J Clin Oncol. 2016;34:3749-3757.
  4. Palefsky JM. Human papillomavirus-associated anal and cervical cancers in HIV-infected individuals: incidence and prevention in the antiretroviral therapy era. Curr Opin HIV AIDS. 2017;12:26-30.
  5. Mosicki 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.
  6. de Vries HJC, Steenbergen RDM. The effect of ART on cervical precursor lesions [published online October 26, 2017]. Lancet HIV.  doi:10.1016/S2352-3018(17)30189-3
  7. Kelly H, Weiss HA, Benavente Y, de Sanjose S, Mayaud P; ART and HPV Review Group. Association of antiretroviral therapy with high-risk human papillomavirus, cervical intraepithelial neoplasia, and invasive cervical cancer in women living with HIV: a systematic review and meta-analysis [published online October 26, 2017]. Lancet HIV. doi:10.1016/S2352-3018(17)30149-2
  8. Tugizov SM, Herrera R, Chin-Hong P, et al. HIV-associated disruption of mucosal epithelium facilitates paracellular penetration by human papillomavirus. Virology. 2013;446:378-388.
  9. Masur H, Brooks JT, Benson CA, Holmes KK, Pau AK, Kaplan JE; National Institutes of Health; Centers for Disease Control and Prevention; HIV Medicine Association of the Infectious Diseases Society of America. Prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: updated guidelines from the Centers for Disease Control and Prevention, National Institutes of Health, and HIV medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014;58:1308-1311.
  10. Coghill AE, Shiels MS, Suneja G, Engels EA. Elevated cancer-specific mortality among HIV-infected patients in the United States. J Clin Oncol. 2015;233:2376-2383.
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