The following are selected treatment briefs from the 6th Conference on Retroviruses and Opportunistic Infections. While these studies are of special interest to women, they do not exhaustively cover all the gender-specific information presented at the conference or reviewed in this issue.
Women have long reported menstrual irregularities associated with HIV infection, including shortened or lengthened time between menstruation, heavier or lighter flow of menstrual blood and other irregularities. Research findings, however, have been yielding conflicting results regarding the association between menstrual irregularity and HIV status. A new study confirms an association and observes that irregularities appear more frequently as HIV disease progresses.
Included in this report were 802 HIV-positive and 273 HIV-negative women from two large studies (HIV Epidemiology Study or HERS and Women's Interagency HIV Study or WIHS). Women self-reported information about their menstrual cycle over the course of six months.
Overall, the study found that HIV-positive women, who were otherwise healthy, had high CD4+ cell counts, were not experiencing unwanted weight loss (wasting syndrome) and not using/abusing drugs were unlikely to have menstrual irregularities. As HIV disease progresses, however, there does appear to be some effect of HIV on hormones, as measured by increased incidence of menstrual irregularities. Women with lower CD4+ cell counts (below 200) were 50% more likely to have longer menstrual cycles (over 40 days) than women with counts above 200. Women with high HIV levels (above 150,000 copies/ml) had the most variability in their menstrual cycle, shorter and longer times between cycles with a large amount of unpredictability.
This study confirms a relationship between HIV infection and changes in the menstrual cycle, which becomes more pronounced as HIV disease progresses, CD4+ cell counts fall below 200 and HIV levels increase. The study confirms that other factors are important determinants of menstrual irregularity and should be considered when and if they occur. These include drug use, poor nutrition, severe medical illness and weight loss associated with chronic illness. A number of other factors have also been identified in other studies (see Menstrual Irregularities Co-Factors Chart below).
|Menstrual Irregularity Co-Factors Chart|
|Younger and older age are both associated with menstrual irregularities. Young women often have irregularities when first beginning to menstruate, sometimes lasting through puberty. Older women, especially those going through menopause, also commonly have irregularities. On either end of this age spectrum, hormone therapy (e.g. progesterone/estrogen) may help to regulate menstrual cycles. However, it is not known if trying to regulate these natural changes is helpful.|
|Body Mass Index||Women who are very thin, malnourished, or who generally have extremely low levels of body fat often have menstrual irregularities, particularly increased time between menstruation and/or very light bleeding during periods. For women who are thin because of malnutrition and unwanted weight loss issues, attention to treating unwanted weight loss can help to regulate the cycle.|
|Drug Use (substance use/abuse)||Injection drug and other substance use are associated with changes in menstrual cycles.|
|Illnesses and Infections||Some illnesses, and side effects from drugs used to treat them, can influence menstrual cycles. Inflammatory and infectious conditions (e.g. vaginitis and pelvic inflammatory disease) can also affect regularity.|
|Dysplasia||Dysplasia (e.g. vulvar, vaginal, cervical and ovarian) is associated with changes in menstrual cycles.|
|Race||While this particular study only looked at whites, Latinas and African Americans, there did appear to be more menstrual irregularities among African Americans compared to the other groups. It may be, in this particular study, that other factors confounded the ability to truly isolate any differences caused by race difference. However, even this hint of a racial differential warrants further study.|
It is not surprising that there is a relationship between HIV infection and menstrual irregularities. Male hormone irregularities (testosterone deficiencies) are associated with HIV disease progression, fatigue and wasting syndrome. Similarly, female hormone changes, as measured by increases in menstrual irregularities, are associated with advanced HIV-disease and wasting syndrome. The question now is what to do about these changes. Will hormone replacement therapy (e.g. estrogen/progesterone) help regulate menstrual cycles and/or improve symptoms associated with hormone imbalances such as fatigue and decreased sexual drive? Should women receive anabolic steroids (like testosterone) when they experience signs of unwanted weight loss and/or decrease in sexual energy? Now that menstrual irregularities have been documented, and the group of women likeliest to experience them have been defined, studies looking at therapies to intervene and correct these irregularities should proceed quickly. Activist attention is needed to make it happen.
Human Papilloma Virus
Human Papilloma Virus (HPV) is a sexually transmitted disease that causes anal and genital warts and is associated with anal and cervical dysplasia. It is a common infection, particularly among women with HIV. Several studies confirm previous findings that women with HIV, particularly those with low CD4+ cell counts, have increased frequency and severity of HPV-associated cervical dysplasia.
One study examined the incidence of HPV-associated lesions in women without HPV who were enrolled in a study from 1991-98. Every six months, 369 HIV-positive and 334 HIV-negative volunteers had gynecological (GYN) exams and colposcopies. Thirty-one (8%) of HIV-infected and two (1%) of HIV-negative women developed HPV-related lesions throughout follow-up (3.3 years, 3.7 years, respectively). Not only were HIV-positive women more likely to develop HPV-related lesions, but the average time to lesion development was shorter (24 months, 44 months, respectively). Also, the majority (61%) who developed a lesion had a history of cervical intraepithelial neoplasia or CIN. (CIN -- or cervical dysplasia -- is a form of abnormal cell growth of which, at its most severe, is cervical cancer.) The study found that risk factors for lesion development included CD4+ cell counts below 500 and detection of HPV in cervico-vaginal lavage (CVL, a screening procedure).
|"HIV-related immune suppression is a co-factor for the development of HPV and HPV-associated cervical dysplasia. These studies underline the importance of careful and regular GYN screenings for women with HIV, particularly those with CD4+ cell counts below 500."|
Another study examined the relationship between incidence of HPV and immune suppression in 268 female intravenous drug users. In it, 814 HIV-positive and 84 HIV-negative women underwent an average of six HPV measurements. Among 187 women with follow-up visits subsequent to the first measurement, the probability of testing HPV-positive increased dramatically for HIV-positive (78.7%) compared to HIV-negative women (47.5%). It was high among HIV-positive women with CD4+ cell counts below 200 (92.9%). Also, of 107 women evaluated by colposcopies, eleven had biopsies confirming CIN. These results suggest that HIV-infection and its associated immunodeficiency is strongly related to the persistence of HPV which in turn is associated with CIN.
Another study characterized the incidence and progression of HPV in HIV-infected women with varying levels of immune suppression. Between 3/96 and 7/98, 112 women were evaluated by twice-yearly GYN exams, CVL and STD screenings. In the study, 112 women (63%) had detectable HPV at the initial exam, with another 77 (69%) testing HPV-positive during the course of the study. In addition, 23 (20.5%) were infected with two or more HPV types, and three were infected with a unique or previously unidentified type. These results demonstrate that HPV is highly prevalent and persistent among women with HIV. They demonstrate that HPV types may be distinct in women with HIV.
Comments on HPV
These studies confirm that HIV-related immune suppression is a co-factor for the development of HPV and HPV-associated cervical dysplasia. Other co-factors include smoking, age of first sexual intercourse and, possibly, hormonal issues. These studies underline the importance of careful and regular GYN screenings for women, particularly those with CD4+ cell counts below 500 (e.g. at least every six months).
Treatment of Recurrent Cervical Dysplasia (CIN)
Previous studies confirm that abnormal cell growth in the cervix (cervical dysplasia), associated with cervical cancer, is more common and potentially more aggressive among women living with HIV compared to uninfected women. Women with HIV have extremely high recurrence rates of cervical dysplasia after standard treatment (39-87% among HIV-positive women vs. 0_18% among HIV-negative women). A study of the AIDS Clinical Trials Group (ACTG 200) examined the safety and effectiveness of a therapy called 5-Fluorouracil (5-FU) for preventing recurrent cervical dysplasia (CIN). 5-FU has been successful in treating skin lesions in HIV-negative people as well as vaginal dysplasia in women with immune suppression not associated with HIV.
One hundred and one women who had received standard treatments for cervical dysplasia (CIN grades 2 or 3) received either 5% 5-FU or no therapy and were followed for a year and a half (18 months). Those receiving 5-FU received one 2 gram application intra-vaginally at bedtime every two weeks for six months. The medication was not administered during menstruation. Pap smears and colposcopies were scheduled at regular intervals during the 18 months of follow-up.
Of the 50 women who received 5-FU, 14 (28%) developed cervical dysplasia recurrence, compared to 24 (47%) of the 51 women in the observation arm. Most significantly, 5-FU therapy was significantly correlated to prolonged time to recurrence of CIN and decreased probability of developing high grade CIN, which requires more aggressive treatment. Additionally, 5-FU therapy reduced recurrent cervical dysplasia with minimal side effects (vaginal discharge was the most common, occurring in six women). These results suggest that this treatment should be offered to HIV-positive women after therapy for high-grade CIN.
For more information on GYN conditions associated with HIV infection, call the Project Inform Hotline and ask for the new GYN Conditions Discussion Paper.
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