Improving Outcomes in HPV- and HIV-Related Cervical Cancer

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  • Cervical Cancer_ST_77899189

  • The American Cancer Society estimates that >13,000 new cases of invasive cervical cancer will be diagnosed among US women in 2018, with >4000 individuals dying of the disease2; however, the incidence of cervical cancer and risk for death varies significantly by state, largely because of socioeconomic factors and available resources.3 Cervical cancer is most commonly diagnosed in women aged 35 to 44 years, with women <20 years rarely affected.2 Risk extends into older age, and >15% of cervical cancers are diagnosed in women aged >65 years.2 HIV-positive women have a 3-fold increased risk of developing cervical cancer vs the general population.4 It has been suggested that this increased risk is attributed to their weakened immune system, reducing their bodies' ability to fight viruses that have been linked to carcinogenesis, such as HPV, which has been observed in 99.7% of all cervical cancers.4,5 Photo Credit: Centers for Disease Control and Prevention.

    Epidemiology of Cervical Cancer

    The American Cancer Society estimates that >13,000 new cases of invasive cervical cancer will be diagnosed among US women in 2018, with >4000 individuals dying of the disease2; however, the incidence of cervical cancer and risk for death varies significantly by state, largely because of socioeconomic factors and available resources.3 Cervical cancer is most commonly diagnosed in women aged 35 to 44 years, with women <20 years rarely affected.2 Risk extends into older age, and >15% of cervical cancers are diagnosed in women aged >65 years.2

    HIV-positive women have a 3-fold increased risk of developing cervical cancer vs the general population.4 It has been suggested that this increased risk is attributed to their weakened immune system, reducing their bodies' ability to fight viruses that have been linked to carcinogenesis, such as HPV, which has been observed in 99.7% of all cervical cancers.4,5

    Photo Credit: Centers for Disease Control and Prevention.

  • Cervical screening enables early identification and curative treatment of precancerous lesions, significantly reducing the cervical cancer death rate, but not all women are being adequately screened. To improve cervical cancer screening, numerous guidelines have been issued, with recommendations generally in agreement. Among available US guidelines, those by the USPSTF will be the most recently updated; a draft recommendation statement was released in October 2017.6 The USPSTF's draft statement recommends starting screening at age 21 years in the general population, and screening with cervical cytology alone until age 29 years.6 In women aged 30 to 65 years, cervical cytology alone can continue every 3 years, or high-risk HPV testing alone can be performed every 5 years, which changes previous recommendations requiring concomitant cervical cytology. After age 65 years, screening can be stopped for those with adequate prior screenings and no increased risk for cervical cancer.6 Photo Credit: Centers for Disease Control and Prevention.

    Latest Cervical Cancer Screening Recommendations

    Cervical screening enables early identification and curative treatment of precancerous lesions, significantly reducing the cervical cancer death rate, but not all women are being adequately screened. To improve cervical cancer screening, numerous guidelines have been issued, with recommendations generally in agreement. Among available US guidelines, those by the USPSTF will be the most recently updated; a draft recommendation statement was released in October 2017.6

    The USPSTF's draft statement recommends starting screening at age 21 years in the general population, and screening with cervical cytology alone until age 29 years.6 In women aged 30 to 65 years, cervical cytology alone can continue every 3 years, or high-risk HPV testing alone can be performed every 5 years, which changes previous recommendations requiring concomitant cervical cytology. After age 65 years, screening can be stopped for those with adequate prior screenings and no increased risk for cervical cancer.6

    Photo Credit: Centers for Disease Control and Prevention.

  • More than 29,000 cervical cancer cases could be prevented with HPV vaccination.7 The CDC recommends vaccinating girls and boys against HPV starting at age 11 or 12 years.7 Females aged 13 to 26 years and males aged 13 to 21 years who have not been previously vaccinated can also be given the vaccine. In addition, vaccination can be extended to age 26 years in the following populations: bisexual or gay men who are sexually active or intend to be sexually active, transgender persons, and those with HIV or other immunocompromise.7 Three HPV vaccines are currently approved by the FDA: Gardasil, Cervarix, and Gardasil 9.8 All 3 protect against HPV 16 and 18, which have been implicated in 70% of all cervical cancers. Gardasil and Gardasil 9 also protect against HPV 6 and 11, which are responsible for 90% of genital warts. In addition, Gardasil 9 protects against 5 other high-risk HPV subtypes, including 31, 33, 45, 52, and 58, and it may be offered to those who previously received Gardasil.8 Photo Credit: Centers for Disease Control and Prevention.

    Latest HPV Vaccine Recommendations

    More than 29,000 cervical cancer cases could be prevented with HPV vaccination.7 The CDC recommends vaccinating girls and boys against HPV starting at age 11 or 12 years.7 Females aged 13 to 26 years and males aged 13 to 21 years who have not been previously vaccinated can also be given the vaccine. In addition, vaccination can be extended to age 26 years in the following populations: bisexual or gay men who are sexually active or intend to be sexually active, transgender persons, and those with HIV or other immunocompromise.7

    Three HPV vaccines are currently approved by the FDA: Gardasil, Cervarix, and Gardasil 9.8 All 3 protect against HPV 16 and 18, which have been implicated in 70% of all cervical cancers. Gardasil and Gardasil 9 also protect against HPV 6 and 11, which are responsible for 90% of genital warts. In addition, Gardasil 9 protects against 5 other high-risk HPV subtypes, including 31, 33, 45, 52, and 58, and it may be offered to those who previously received Gardasil.8

    Photo Credit: Centers for Disease Control and Prevention.

  • HPV Screening Recommendations in HIV-Positive Women

    HPV Screening Recommendations in HIV-Positive Women

    More stringent cervical cancer screening is recommended for HIV-positive women.9 In those aged <30 years, cervical cytology should start within 1 year of sexual activity onset and no later than age 21 years, regardless of mode of transmission.9 Women with HIV diagnosed at ≥21 years should undergo cervical cytology at the time of HIV diagnosis, with concomitant HPV screening an option in those aged ≥30 years. Screening should continue throughout the woman's lifetime.

    If cervical cytology is normal at baseline, retesting at 6 months should be considered and performed annually until 3 consecutive tests are normal, which enables extension to every 3 years. If testing is abnormal, repeat cytology or HPV testing can be performed. Those with normal results on cotesting can be screened again in 3 years, whereas those with a normal cytology and positive HPV should repeat screening in 1 year. If at any time HPV 16 and/or 18 are detected, colposcopy is recommended.9

  • Gardasil and Cervarix have good immunogenicity and safety in people with HIV, but efficacy studies and data on Gardasil 9 are lacking.10 Vaccination is likely most beneficial in HPV-naive individuals, and it can be administered to those as young as 9 years.10 In HIV-positive children aged >7 to 96% vs 0% receiving placebo.11 However, antibody levels for HPV 6 and 18 were 30% to 50% lower vs age-matched uninfected controls.11 Vaccination is thought less effective after sexual activity onset because of the likelihood of HPV exposure.9 However, good safety and antibody response has been shown in HIV-positive women aged 16 to 23 years who were negative for the HPV subtypes covered.12 Also, because most HIV-infected women up to age 45 years have not had exposure to all HPV subtypes covered by currently available vaccines, vaccination may offer some protection, but more studies are needed.13

    HPV Vaccination in HIV-Positive Patients

    Gardasil and Cervarix have good immunogenicity and safety in people with HIV, but efficacy studies and data on Gardasil 9 are lacking.10 Vaccination is likely most beneficial in HPV-naive individuals, and it can be administered to those as young as 9 years.10 In HIV-positive children aged >7 to 96% vs 0% receiving placebo.11 However, antibody levels for HPV 6 and 18 were 30% to 50% lower vs age-matched uninfected controls.11

    Vaccination is thought less effective after sexual activity onset because of the likelihood of HPV exposure.9 However, good safety and antibody response has been shown in HIV-positive women aged 16 to 23 years who were negative for the HPV subtypes covered.12 Also, because most HIV-infected women up to age 45 years have not had exposure to all HPV subtypes covered by currently available vaccines, vaccination may offer some protection, but more studies are needed.13

  • HIV-positive women are at increased risk for immunosuppression. A relationship between lower CD4+ level (<500/mm3) and increased prevalence of cervical and anal HPV infection has been reported, with risk highest among women with CD4 levels <200/mm3.10 Women who progress to cervical cancer often show significant T-cell dysfunction, especially if they are HIV treatment-naive.10 In 1 study, HIV-positive women with cervical cancer, which included some previously treated with highly active antiretroviral therapy (HAART), were found to have a median CD4 count of 354/mm3 (range, 33-1249/mm3).14 Low CD4 counts before cervical cancer treatment increase the risk for complications, including neutropenia-related opportunistic infections and reactivation of dormant viral infections.10 Vaccination against varicella, influenza, and pneumococcal disease may be beneficial for some HIV-positive patients before cervical cancer treatment.10 In addition, current hepatitis B immune status should be considered and HAART optimized to increase CD4 counts.10

    Immunosuppression in HIV-Positive Women

    HIV-positive women are at increased risk for immunosuppression. A relationship between lower CD4+ level (<500/mm3) and increased prevalence of cervical and anal HPV infection has been reported, with risk highest among women with CD4 levels <200/mm3.10 Women who progress to cervical cancer often show significant T-cell dysfunction, especially if they are HIV treatment-naive.10 In 1 study, HIV-positive women with cervical cancer, which included some previously treated with highly active antiretroviral therapy (HAART), were found to have a median CD4 count of 354/mm3 (range, 33-1249/mm3).14

    Low CD4 counts before cervical cancer treatment increase the risk for complications, including neutropenia-related opportunistic infections and reactivation of dormant viral infections.10 Vaccination against varicella, influenza, and pneumococcal disease may be beneficial for some HIV-positive patients before cervical cancer treatment.10 In addition, current hepatitis B immune status should be considered and HAART optimized to increase CD4 counts.10

  • Surgery, radiation, and chemotherapy alone or in combination are mainstays of treatment in cervical cancer. Per the National Comprehensive Cancer Network, modifications to treatment should not be made solely based on HIV status.16 In those deemed surgical candidates, careful presurgical preparation is essential to optimize perioperative recovery, as HIV-positive women are at increased risk for hemorrhage and infections.10 Use of minimally invasive techniques might reduce these risks.10 In locally advanced disease, chemoradiation is generally used because of an improved survival benefit vs radiotherapy alone, although data in HIV-positive women are limited.10 Patients receive external beam radiation and/or brachytherapy, along with cisplatin alone or with fluorouracil.16 Vigilant monitoring is essential because of the increased risk for immunosuppression and toxicity, as chemotherapy and HAART may be metabolized via the same pathway, impairing drug clearance.17

    Treatment of HIV-Positive Patients With Cervical Cancer

    Surgery, radiation, and chemotherapy alone or in combination are mainstays of treatment in cervical cancer. Per the National Comprehensive Cancer Network, modifications to treatment should not be made solely based on HIV status.16 In those deemed surgical candidates, careful presurgical preparation is essential to optimize perioperative recovery, as HIV-positive women are at increased risk for hemorrhage and infections.10 Use of minimally invasive techniques might reduce these risks.10

    In locally advanced disease, chemoradiation is generally used because of an improved survival benefit vs radiotherapy alone, although data in HIV-positive women are limited.10 Patients receive external beam radiation and/or brachytherapy, along with cisplatin alone or with fluorouracil.16 Vigilant monitoring is essential because of the increased risk for immunosuppression and toxicity, as chemotherapy and HAART may be metabolized via the same pathway, impairing drug clearance.17

  • Survival outcomes in patients with HIV and cervical cancer are not well known because data are limited. However, outcomes may be somewhat poorer vs the HIV-negative population because lower cervical cancer treatment completion rates have been observed in this population.10 Likelihood of treatment completion is often affected by adverse effects (AEs), particularly those grade 3 or higher. Because HIV-positive patients have a higher risk for many AEs, including more severe hematological AEs, careful pretreatment planning and vigilant monitoring are necessary to improve the likelihood of treatment completion. When HIV is well-managed, and patients can complete treatment, survival outcomes appear similar to those of the general population.10 Further studies are needed to better assess barriers to treatment completion, including immune dysfunction, AEs, and healthcare-related factors such as physician bias or care access issues.10 Photo Credit: National Cancer Institute/Science Source.

    Survival Outcomes in Comorbid HIV and Cervical Cancer

    Survival outcomes in patients with HIV and cervical cancer are not well known because data are limited. However, outcomes may be somewhat poorer vs the HIV-negative population because lower cervical cancer treatment completion rates have been observed in this population.10 Likelihood of treatment completion is often affected by adverse effects (AEs), particularly those grade 3 or higher. Because HIV-positive patients have a higher risk for many AEs, including more severe hematological AEs, careful pretreatment planning and vigilant monitoring are necessary to improve the likelihood of treatment completion.

    When HIV is well-managed, and patients can complete treatment, survival outcomes appear similar to those of the general population.10 Further studies are needed to better assess barriers to treatment completion, including immune dysfunction, AEs, and healthcare-related factors such as physician bias or care access issues.10

    Photo Credit: National Cancer Institute/Science Source.

  • A multidisciplinary approach to care that addresses physical and psychosocial needs is essential for patients with HIV, especially in the setting of comorbid cervical or other cancer. HIV-positive patients who receive additional services, such as case management and mental health services, are 1.3 to 3 times more likely to be retained in HIV care than those who do not access these services.18 A multidisciplinary approach can also lead to timelier cervical cancer treatment. In Botswana, a middle-income country in which more than two-thirds of cervical cancers occur in HIV-positive women, a multidisciplinary care model significantly cut lag time between diagnosis and treatment from 108 to 39 days.19 The model involved weekly meetings across care providers, including radiation and clinical oncologists, gynecologists, nurses, and palliative care specialists, to discuss patient cases and care plans and facilitate completion of required paperwork.

    Multidisciplinary Approach to Care of Comorbid HIV and Cervical Cancer

    A multidisciplinary approach to care that addresses physical and psychosocial needs is essential for patients with HIV, especially in the setting of comorbid cervical or other cancer. HIV-positive patients who receive additional services, such as case management and mental health services, are 1.3 to 3 times more likely to be retained in HIV care than those who do not access these services.18 A multidisciplinary approach can also lead to timelier cervical cancer treatment. In Botswana, a middle-income country in which more than two-thirds of cervical cancers occur in HIV-positive women, a multidisciplinary care model significantly cut lag time between diagnosis and treatment from 108 to 39 days.19 The model involved weekly meetings across care providers, including radiation and clinical oncologists, gynecologists, nurses, and palliative care specialists, to discuss patient cases and care plans and facilitate completion of required paperwork.

  • Large, randomized, multicenter, prospective cervical cancer treatment trials are lacking for HIV-positive patients, and data to guide diagnosis and treatment have largely come from cohort studies.10 In addition, no novel cancer treatments, such as targeted agents, are currently being tested in HIV-positive patients, and HIV positivity continues to be an exclusion criterion in cancer treatment research.10 However, there is a glimmer of hope that this may be changing. A phase 3 randomized study in South Africa is currently recruiting HIV-positive and HIV-negative patients to assess modulated electro-hyperthermia plus chemoradiation for locally advanced cervical cancer (ClinicalTrials.gov identifier: NCT03332069).20 In addition to cancer outcomes, researchers will assess whether modulated electro-hyperthermia has any effect on HIV disease status, as determined by presence of AIDS-defining illnesses before and after treatment.

    Research Needs

    Large, randomized, multicenter, prospective cervical cancer treatment trials are lacking for HIV-positive patients, and data to guide diagnosis and treatment have largely come from cohort studies.10 In addition, no novel cancer treatments, such as targeted agents, are currently being tested in HIV-positive patients, and HIV positivity continues to be an exclusion criterion in cancer treatment research.10 However, there is a glimmer of hope that this may be changing. A phase 3 randomized study in South Africa is currently recruiting HIV-positive and HIV-negative patients to assess modulated electro-hyperthermia plus chemoradiation for locally advanced cervical cancer (ClinicalTrials.gov identifier: NCT03332069).20 In addition to cancer outcomes, researchers will assess whether modulated electro-hyperthermia has any effect on HIV disease status, as determined by presence of AIDS-defining illnesses before and after treatment.

Scientific evidence has shown links among HIV, human papillomavirus (HPV), and cervical cancer.1 Subsequently, UNAIDS and the World Health Organization have called for leveraging the synergies between these conditions to improve patient outcomes by developing integrated approaches that address HIV, child and adolescent health, sexual and reproductive health and rights, gender equality, and cancer and primary healthcare services to address the interrelated factors that increase the risk for each of these conditions.1 The hope is that widespread use of such strategies can help prevent unnecessary deaths from cervical cancer and bring an end to the AIDS epidemic by 2030.

Compiled by Christina Loguidice

References

  1. HPV, HIV, and cervical cancer: leveraging synergies to save women’s lives. UNAIDS. Published 2016. Accessed January 11, 2018.
  2. Key statistics for cervical cancer. American Cancer Society. Accessed January 11, 2018.
  3. Cervical cancer rates by state. Centers for Disease Control and Prevention. Accessed January 11, 2018.
  4. HIV infection and cancer risk. National Cancer Institute. Reviewed September 14, 2017. Accessed January 11, 2018.
  5. Frumovitz F. Invasive cervical cancer: epidemiology, risk factors, clinical manifestations, and diagnosis. UptoDate. Reviewed December 2017. Accessed January 11, 2018.
  6. Draft recommendation statement: cervical cancer screening. US Preventive Services Task Force. Issued October 2017. Accessed January 11, 2018.
  7. 6 reasons to get HPV vaccine for your child. Centers for Disease Control and Prevention. Updated August 24, 2017. Accessed January 11, 2018.
  8. Human papillomavirus (HPV) vaccines. National Cancer Institute. Reviewed November 2, 2016. Accessed January 11, 2018.
  9. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: human papillomavirus disease. US Department of Health and Human Services. Reviewed July 25, 2017. Accessed January 11, 2018.
  10. Ghebre RG, Grover S, Xu MJ, Chuang LT, Simonds H. Cervical cancer control in HIV-infected women: past, present and future. Gynecol Oncol Rep. 2017;21:101-108.
  11. Levin MJ, Moscicki AB, Song LY, et al; IMPAACT P1047 Protocol Team. Safety and immunogenicity of a quadrivalent human papillomavirus (types 6, 11, 16, and 18) vaccine in HIV-infected children 7 to 12 years old. J Acquir Immune Defic Syndr. 2010;55:197-204.
  12. Kahn JA, Xu J, Kapogiannis BG, et al. Immunogenicity and safety of the human papillomavirus 6, 11, 16, 18 vaccine in HIV-infected young women. Clin Infect Dis. 2013;57:735-744.
  13. Kojic EM, Rana AI, Cu-Uvin S. Human papillomavirus vaccination in HIV-infected women: need for increased coverage. Expert Rev Vaccines. 2016;15:105-117.
  14. Palefsky JM, Holly EA. Chapter 6: Immunosuppression and co-infection with HIV. JNCI Monographs. 2003;31:41-46.
  15. Simonds HM, Wright JD, du Toit N, Neugut AI, Jacobson JS. Completion of and early response to chemoradiation among HIV-positive and HIV-negative patients with locally advanced cervical carcinoma in South Africa: a retrospective cohort study. Cancer. 2012;118:2971-2979.
  16. Cervical Cancer. Version 1.2018. NCCN Guidelines. www.nccn.org/professionals/physician_gls/pdf/cervical.pdf. Accessed January 15, 2017.
  17. Ntekim A, Campbell O, Rothenbacher D. Optimal management of cervical cancer in HIV-positive patients: a systematic review. Cancer Medicine. 2015;4:1381-1393.
  18. Does multidisciplinary care improve health outcomes among people living with HIV and/or HCV? A review of the evidence. CATIE. Accessed January 15, 2018.
  19. Grover S, Chiyapo SP, Puri P, et al. Multidisciplinary gynecologic oncology clinic in botswana: a model for multidisciplinary oncology care in low- and middle-income settings. J Glob Oncol. 2017;3:666-670.
  20. ClinicalTrials.gov. Modulated electro-hyperthermia plus chemo-radiation for locally advanced cervical cancer patients in South Africa (mEHT). NCT03332069. Accessed January 15, 2017.

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