February 25, 2016
Cervical intraepithelial neoplasia (CIN), a cervical cell abnormality that could lead to cervical cancer, developed at a higher rate in HIV-positive women than HIV-negative women in a nationwide study in Denmark.1 But CIN did not develop more often in HIV-positive women when researchers looked only at women with a normal initial Pap test who followed cervical cancer screening guidelines. And invasive cervical cancer did not arise in HIV-positive women more than in HIV-negative women.
Cervical cancer is an AIDS-defining cancer. Previous studies found that it affects HIV-positive women more than HIV-negative women. Abnormal cervical cell growth -- called cervical dysplasia or cervical intraepithelial neoplasia (CIN) -- develops before cervical cancer and can lead to cervical cancer. Infection with human papillomavirus (HPV), a sexually transmitted virus, can cause CIN and cervical cancer.
The Pap test can help detect abnormal cervical cells before they develop into cervical cancer, and treatment can prevent cancer. If cervical cancer has already developed but is still in an early stage, it can often be treated successfully.2 The American Cancer Society recommends that all women 21 or older get a Pap test every 3 years.3 But because cervical cancer is more common in women with HIV, U.S. health authorities recommend Pap testing twice in the year after a woman tests positive for HIV and once a year after that.4
In Denmark, where Pap testing is widely available and free, fewer than half of HIV-positive women get a Pap test every year. Fewer than 5% get two Pap tests in the year after they test positive for HIV. A study of 2417 women in 18 U.S. states found that one quarter had not had a Pap test in the past year.5 To learn whether low Pap test rates affect chances of CIN or cervical cancer in women with HIV, researchers in Denmark conducted this nationwide study.1
All HIV-positive people in Denmark receive free medical care at one of eight centers that specialize in HIV infection. As in the United States, HIV-positive women are advised to have two Pap tests in the first year after testing positive for HIV and once a year after that. Women without HIV receive a written invitation to have a Pap test every 3 years if they are 23 to 49 years old and every 5 years if they are 50 to 65.
Since January 1995 all HIV-positive people in care at one of the eight HIV centers in Denmark have been part of the Danish HIV Cohort Study. Personal and medical data for each person go into a national database once a year. This cervical cancer study focused on all women 16 years old or older when they tested positive for HIV. The researchers matched each HIV-positive woman to 15 HIV-negative women the same age. No HIV-positive or negative women had cervical cancer in the past or a hysterectomy (removal of the womb).
Then the researchers checked national databases to see which women developed cervical intraepithelial neoplasia (CIN) or invasive cervical cancer. They rated CIN severity by a standard system in which CIN1 is the least severe form and CIN3 is the most severe. The researchers calculated time from when women entered the study to development of CIN1 or worse, CIN2 or worse, CIN3 or worse, or cervical cancer. They used a standard statistical test to compare rates of new CIN or cervical cancer in HIV-positive and HIV-negative women. Next they compared rates of new CIN or cervical cancer only in women whose first Pap test was normal. The research team also compared new CIN or cervical cancer rates in HIV-positive versus HIV-negative women whose first Pap test was normal and who followed national Pap test guidelines (a Pap test every 3 years for women 23 to 49 years old and every 5 years for women 50 to 65). In this group of women who followed screening guidelines, the researchers determined whether being infected with HIV affected chances of following national Pap test guidelines.
Finally, the researchers used an accepted statistical method to identify risk factors for CIN or cervical cancer in women with HIV. This method considers several risk factors at the same time, including age, ethnic background, how women became infected with HIV, and whether women smoked. One analysis considered all these factors plus CD4 count. A separate analysis considered all these factors plus viral load.
The study involved 1140 women with HIV and 17,046 without HIV. Both groups had a median (midpoint) age of 33.6 years when they entered the study, and both groups had a median observation time of more than 9 years. About half of the women with HIV were white, one third black, and 11% Asian. Among women with HIV, 43% smoked during the study period or in the past, 34% never smoked, and the researchers did not have smoking information on the other 23%. (Smoking raises the risk of CIN, cervical cancer, and many other cancers.)
CIN or cervical cancer developed more often in women with HIV than in women without HIV. Rates in women with HIV versus without HIV were 14.3% versus 4.3% for CIN1 or worse, 11.3% versus 3.6% for CIN2 or worse, and 6.8% versus 2.5% for CIN3 or worse (Figure 1). Invasive cervical cancer developed in fewer than 1% of women, but the cancer rate was twice higher in women with HIV -- 0.4% versus 0.2%. Statistical analysis that considered several risk factors at the same time identified two factors that raised the risk of CIN in women with HIV: age 18 to 30 versus older and current CD4 count below 200 versus over 350.
Figure 1. A nationwide comparison of HIV-positive and negative women in Denmark found higher rates of new cervical intraepithelial neoplasia (CIN, a precancer abnormality) in the women with HIV. The differences in CIN3 and cancer rates are not statistically significant, meaning that chance could explain these differences.
The study group included 841 HIV-positive women and 11,067 HIV-negative women who had a normal Pap test the first time they got tested. Among these women, rates of new CIN1 or worse or CIN2 or worse were higher in women with than without HIV: 7.4% versus 3.8% for CIN1 or worse, and 6.1% versus 3.2% for CIN2 or worse. But HIV-positive women did not differ much from HIV-negative women in rates of new CIN3 or worse or cervical cancer. In these women, statistical analysis that considers several risk factors at the same time determined that HIV-positive women had more than a twice higher risk of CIN1 or worse or CIN2 or worse (Figure 2). But women with HIV did not have a higher risk of CIN3 or worse or cervical cancer.
Figure 2. A comparison of HIV-positive and negative women the same age found that women with HIV had more than a doubled risk of CIN1 or worse or CIN2 or worse, regardless of whatever other risk factors a woman had. (Illustration of cervix from Servier PowerPoint Image Bank.)
The researchers counted 144 HIV-positive women (12.6% of the whole group) who followed national Pap test guidelines and had a normal first Pap test. A much higher proportion of HIV-negative women (28%) followed national guidelines and had a normal first Pap test. Statistical analysis that considered several factors at the same time found no difference in rates of new CIN when comparing these HIV-positive and negative women. While 67% of HIV-positive women had a second Pap test within 39 months of their first test, 83% of HIV-negative women had a second Pap test within 39 months of their first test.
This large and long study comparing HIV-positive and HIV-negative women throughout Denmark found that the HIV group had more than a twice higher risk of cervical intraepithelial neoplasia (CIN), cell changes that can develop into cervical cancer. The study also found that HIV-positive women follow guidelines on when to get Pap tests much less often than HIV-negative women. But HIV-positive women whose first Pap test was normal and who followed Pap test guidelines did not have a higher risk of CIN than HIV-negative women who followed Pap test guidelines. That finding underlines the importance of regular Pap testing by all women.
A long but smaller study comparing HIV-positive and negative women in the United States found higher rates of CIN2 or worse or CIN3 or worse in women with HIV.6 As part of this study, all women had a Pap test twice a year. CIN3 or worse developed much less often 2 years after women started regular Pap testing. But HIV-positive women with a CD4 count below 200 ran a higher risk of CIN2 or worse or CIN3 or worse than women without HIV. Thus both the Denmark study and the U.S. study linked a low CD4 count to a higher risk of CIN. Boosting the CD4 count by starting antiretroviral therapy could be one way to lower the risk of CIN and cervical cancer.
Both studies also show that getting the Pap test regularly lowers chances of CIN or cervical cancer. The American Cancer Society recommends four other steps women can take to lower their risk of cervical cancer:7
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