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HIV therapy cuts risk of possibly dangerous changes in cervix and cervical cancer.

Combined analysis of 31 studies found that taking antiretroviral therapy * lowered chances of cervical cancer in women with HIV. (1) Antiretroviral therapy also reduced chances of some potentially dangerous precancer changes in the cervix and chances of infection with high-risk human papillomavirus (HPV), which can lead to cervical cancer.

Cancer of the cervix is an AIDS cancer and among the most common cancers in women with HIV infection. (2) High-risk types of HPV, a virus that can lead to cervical cancer and other cancers, is more common in HIV-positive women than in HIV-negative women. (3) Women with HIV also run a higher risk that cervical intraepithelial neoplasia (CIN), a precancer change in cervical cells, will get worse. (4)

People with HIV began using 3- or 4-drug combinations of antiretrovirals around 1996. Over the next 20 years, these combinations became stronger and easier to take. Today most people who start antiretroviral therapy reach an undetectable viral load and gain CD4 cells. Because the impact of antiretroviral therapy on high-risk HPV, precancer changes in cervical cells, and cervical cancer is poorly understood, researchers in Europe conducted this review.

How the study worked. The study team searched online databases to find studies presented since 1996 that explored the impact of antiretroviral therapy on rates of high-risk HPV, CIN, squamous intraepithelial lesions (SIL), and invasive cervical cancer (see "Cervical cancer-related abbreviations used in this article"). They grouped articles according to whether they involved antiretroviral impact on (1) current rate of high-risk HPV, (2) current rate, new-detection rate, progression (worsening), or regression of CIN or SIL, or (3) new-detection rate of invasive cervical cancer

The researchers combined findings on women in various groups of studies. Then they used standard statistical methods to determine whether women taking antiretroviral therapy had a higher or lower chance of high-risk HPV, CIN, SIL, or cervical cancer than women not taking antiretroviral therapy. Some of these statistical analyses determined the impact of antiretroviral therapy regardless of whatever other risk factors a woman had for high-risk HPV, CIN, SIL, or cervical cancer.

What the study found. Researchers found 19 studies about antiretroviral therapy and high-risk HPV and 33 studies about antiretroviral therapy and CIN, SIL, or cervical cancer. The high-risk HPV studies included 6537 women with HIV, 3677 (56%) who were taking antiretroviral therapy, 2032 (31%) who had never taken antiretroviral therapy, and 828 (13%) just starting antiretroviral therapy.

Combining results of all women in the high-risk HPV studies, statistical analysis determined that women taking antiretroviral therapy had about a 20% lower chance of high-risk HPV infection than women who never took antiretrovirals. (Providers see note 5 for odds ratios or hazard ratios and 95% confidence intervals.) When the analysis considered only 3 studies from Europe or North America, women taking antiretroviral therapy had about a 25% lower chance of high-risk HPV than women who never took antiretrovirals. (5)

Four studies tested women for high-risk HPV before and after they started antiretroviral therapy. These studies found about 20% lower odds of high-risk HPV after women started antiretrovirals. (5) Further analysis found a lower rate of high-risk HPV in women who took antiretroviral therapy for 2 years or more than in women who got treated for a shorter period or not at all.

Combining results of studies involving the impact of antiretroviral therapy on cervical changes (CIN or SIL) or cervical cancer produced several additional findings of the benefits of taking antiretrovirals:

* Combined results of 3 studies determined that women taking antiretrovirals for 2 or more years versus fewer years or not at all had about a 30% lower rate of more advanced CIN. (5)

* Combined analysis of 10 studies suggested that taking antiretroviral therapy lowered the new-detection rate of SIL about 25%. (5)

* Combined analysis of 6 studies suggested that women taking antiretroviral therapy had about a 35% lower risk of worsening SIL. (5)

* Combined analysis of 6 studies suggested that women who took antiretrovirals had about a 60% higher chance that their SIL or CIN would change back to a less advanced stage. (5)

* A single study of 1048 women determined that those who took antiretrovirals (compared with those who never took antiretrovirals) had about a 70% higher chance SIL would change back to a less advanced stage. (5)

* Combined analysis of 2 studies suggested that women who took antiretrovirals had a 60% lower risk of invasive cervical cancer. (5)

What the findings mean for you. This large and careful analysis combined results of previous studies about how antiretroviral therapy may affect chances of high-risk HPV infection, rates of precancer changes in the cervix (CIN and SIL), and development of invasive cervical cancer. Combining and analyzing results of similar previous studies can give a more accurate picture of changes in health or disease.

The overall findings of this analysis are that starting and continuing antiretroviral therapy (1) may lower the risk of high-risk HPV infection, (2) may help prevent or slow down cervical cell changes that can lead to cervical cancer, and (3) may help prevent development of cervical cancer itself. These are important findings for women with HIV, who run a higher risk of cervical cancer than women without HIV. The findings add to the evidence that promptly starting antiretroviral therapy and continuing steady treatment can prevent AIDS diseases (like cervical cancer) as well as some non-AIDS diseases (like heart disease and bone disease).

Why would antiretroviral therapy help prevent cervical cancer? The most likely explanation is that consistently taking antiretrovirals builds up the immune system, which HIV infection has weakened. A healthy immune system is the first line of defense against cancer, especially those cancers caused by viruses like HPV. Once you start antiretroviral therapy, you should try hard to continue taking your pills regularly every day, exactly as your provider instructs. If you have difficulty keeping to a pill-taking schedule or believe your antiretroviral pills cause problems, talk to your provider immediately so you can work through these challenges together.

HIV infection is one of the main risk factors for cervical cancer. Other risk factors are (1) smoking, (2) using birth control pills for 5 or more years, (3) giving birth to 3 or more children, and (4) having several sex partners. (6) If you smoke, you should work with your HIV provider to make a plan to quit. Also, other sexually transmitted infections are important risk factors for acquiring HPV infection and developing HPV-related cervical changes. People with HIV should be tested for sexually transmitted infections and treated if such infections are found.

If you are a woman with HIV--especially if you have one or more of the other risk factors--there are two things you can do to lower or even eliminate the risk of cervical cancer: (1) Get regular Pap tests and, (2) if you do not already have HPV infection, get the HPV vaccine.

Pap testing is a highly effective way to prevent cervical cancer. Regular Pap testing can spot cell changes in the cervix that may lead to cervical cancer. If cervical cancer has begun, Pap testing can detect it at an early stage that's easier to treat. US HIV experts recommend that women with HIV get the Pap test (1) when they begin care for HIV infection, (2) 6 months after the first test, and (3) every year after that. (7)

Vaccination can prevent infection with high-risk HPV, which can lead to cervical cancer and other cancers. Health authorities recommend the HPV vaccine for (1) all girls and boys starting at age 11, (2) girls and women 13 to 26 years old and boys and men 13 to 21 who have not started or completed the HPV vaccine schedule, and (3) gay or bisexual men, men with HIV, and transgender people up to age 26. (8)

REFERENCES

(1.) Kelly H, Weiss HA, Benavente Y de Sanjose S, Mayaud P, for the 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. Lancet HIV. 2018;5:e45-e58.

(2.) Centers for Disease Control and Prevention. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep. 1992;41(Rr-17):1-19.

(3.) McDonald AC, Tergas AI, Kuhn L, Denny L, Wright TC Jr. Distribution of human papillomavirus genotypes among HIV-positive and HIV-negative women in Cape Town, South Africa. Front Oncol. 2014;4:48.

(4.) Denslow SA, Rositch AF, Firnhaber C, Ting J, Smith JS. Incidence and progression of cervical lesions in women with HIV: a systematic global review. Int J STD AIDS. 2014;25:163-177.

(5.) Selected detailed results for providers: In 20 reports women who took antiretroviral therapy (ART) had lower odds of prevalent high-risk HPV than antiretroviral-naive women (crude odds ratio [OR] 0.82, 95% confidence interval [CI] 0.68 to 0.98). This OR did not change substantially when the analysis considered only studies that adjusted for current or nadir CD4 count or ART duration (adjusted OR [aOR] 0.85, 95% CI 0.73 to 1.00). In three studies in Europe or North America, odds of prevalent high-risk HPV remained lower in the antiretroviral-treated group (aOR 0.74, 95% CI 0.59 to 0.93). In 4 studies of women before and after they started ART, adjusted odds of high-risk HPV were significantly lower after treatment began (aOR 0.79, 95% CI 0.71 to 0.88). Pooled data from 3 African studies found lower prevalence of CIN2+ in women who took ART for 2 or more years versus fewer years or not at all (aOR 0.68, 95% CI 0.49 to 0.94). Pooled analysis of 10 studies found evidence of an association between ART and lower SIL incidence (crude hazard ratio [HR] 0.75, 95% CI 0.56 to 1.00). This association was stronger when the analysis adjusted for time-varying effects of ART (aHR 0.64, 95% CI 0.47 to 0.86). Pooled analysis of 6 studies saw a lower risk of cytology-diagnosed SIL progression (crude HR 0.64, 95% CI 0.56 to 0.74). Results were similar in an analysis restricted to 4 studies that adjusted for time-varying ART (aHR 0.64, 95% CI 0.54 to 0.75). Pooled analysis of 6 studies determined that ART users had about a 60% greater chance of SIL or CIN regression (crude HR 1.61, 95% CI 1.31 to 1.97). This association remained in 5 studies that adjusted for time-varying effects of ART (aHR 1.54, 95% CI 1.30 to 1.82). A single study of 1048 women with a median 18 months of follow-up determined that those who took ART (compared with ART-naive women) had a higher chance of SIL regression (aHR 1.71, 95% CI 1.29 to 2.27). Pooled analysis of 2 studies linked ART to a lower risk of invasive cervical cancer (crude HR 0.40, 95% CI 0.18 to 0.87).

(6.) Centers for Disease Control and Prevention. What are the risk factors for cervical cancer? https://www.cdc.gov/ cancer/cervical/basic info/risk factors.htm

(7.) US Department of Health and Human Services Health Resources and Services Administration. HIV/AIDS Bureau. Guide for HIV/AIDS Clinical Care. April 2014. https://hab.hrsa.gov/sites/default/files/hab/clinicalquality- management/2014guide.pdf

(8.) Centers for Disease Control and Prevention. Vaccines and preventable diseases. HPV vaccine recommendations. https://www.cdc.gov/vaccines/vpd/hpv/hcp/recommendations.html

* Words in boldface are explained in the Technical Word List at the end of this issue.

Cervical cancer-related abbreviations used in this article

Cervical cancer: Cancer usually caused by HPV that forms in the cervix (which connects the upper uterus (the womb) with the vagina, Figure 1) and can be detected by regular Pap tests.

CIN: Cervical intraepithelial neoplasia, abnormal cells on the surface of the cervix usually caused by HPV.

HPV: Human papillomavirus, a virus that can cause abnormal tissue growth, which may develop into anal, cervical, or vaginal cancer or other types of cancer.

High-risk HPV: High-risk HPV includes types of HPV more likely to cause cervical cancer and other kinds of cancer.

SIL: Squamous intraepithelial lesion, abnormal growth of squamous cells on the surface of the cervix.

Source: National Cancer Institute. NCI dictionary of cancer terms. https://www. cancer.gov/publications/dictionaries/cancer-terms

Caption: Figure 1. HPV infection can cause changes in cells of the cervix, which lies between the womb and the vagina, and these changes can develop into cervical cancer. (Illustration from Servier PowerPoint Image Bank, http://smart.servier.com/).
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Title Annotation:ARTICLE 4
Publication:HIV Treatment: ALERTS!
Date:May 1, 2018
Words:2106
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