Women and HIV
Women's Research Roundup
Women with AIDS may have a lower risk of developing breast and uterine cancer, according to a study presented at the 96th annual meeting of the American Association for Cancer Research held April 16-20 in Ahaheim. James Goedert and colleagues compared data from 77,369 women with AIDS (from five years before they received an AIDS diagnosis until ten years after) with several million general-population cancer records. Among the women with AIDS, 274 developed breast cancer, 31 developed ovarian cancer, and 29 developed uterine cancer. The incidence (new cases) of breast cancer among both pre- and post-menopausal women with AIDS was 32% lower than among women at large (27% lower after adjusting for differences in childbearing); the incidence of uterine cancer was 40% lower, while the rate of ovarian cancer was similar.
The reasons for these differences are not clear, but the researchers suggested that they may be related to reduced body fat and altered estrogen and androgen (female and male hormone) levels in women with AIDS. Importantly, the difference in breast cancer rates was greatest early in the AIDS epidemic and has become very small since the advent of HAART, suggesting that antiretroviral therapy modifies whatever factors led to lower cancer rates in the pre-HAART era.
According to a report in the December 15, 2004 issue of the Journal of Acquired Immune Deficiency Syndromes (JAIDS), HIV positive women are at greater risk of herpes zoster (shingles) than HIV negative women, even when receiving highly active antiretroviral therapy (HAART). Herpes zoster, caused by the varicella-zoster virus, is a common opportunistic illness (OI) associated with immunodeficiency. Although previous studies have shown an increased incidence of herpes zoster after initiating HAART, few data were available on the effect of long-term antiretroviral therapy on its occurrence.
The JAIDS report involved an analysis of 1,832 HIV positive and 489 HIV negative women in the Women's Interagency HIV Study (WIHS) from six research sites in Chicago, New York, Washington, DC, and California. All women were screened at six-month intervals for a followup period of up to 7.5 years. The study relied on self-reported diagnoses of herpes zoster; medical records were not used to verify reported cases. The majority (68%) of women with HIV started HAART during the follow-up period.
Marshall Glesby, MD, and colleagues found that in the HIV positive group, 337 women (18%) reported at least one case of herpes zoster, compared with only 7 women (1%) in the HIV negative group. HIV positive women were more likely to be diagnosed with the condition regardless of CD4 cell count. Those with CD4 cell counts below 200 cells/mm3 were nearly 25 times more likely to develop shingles than HIV negative women. HIV positive women with high CD4 cell counts (greater than 750 cells/mm3) had nearly a nine times greater risk. Similar results have been reported in men. Based on the WIHS results, the authors concluded that herpes zoster -- unlike many other OIs -- likely will continue to be a problem for HIV positive women on HAART.
High rates of human papillomavirus (HPV) infection have been reported in HIV positive women. HPV causes genital warts and some strains can cause cervical and anal dysplasia (abnormal tissue changes), which are precursors of cervical and anal cancer. Routine cervical Pap smears are a standard component of gynecological care, but the optimal use of anal Pap smears in HIV positive women has not been defined.
In a poster presented at the 12th Conference on Retroviruses and Opportunistic Infections this past February in Boston, Thomas Young, MS, NP, and colleagues from the University of California at San Francisco reported that cervical and anal Pap screening are both important in the care of women with HIV. Their retrospective study (abstract 900) analyzed the results of 217 cervical and 268 anal Pap smears from 161 women screened between January 2000 and July 2004 at San Francisco General Hospital. Of these women, 41% were on continuous antiretroviral therapy. Half of the women were "white," 29% were African American, 15% were Latina, and 4% were of Asian descent. The results of cervical and anal Pap screens were considered "paired" in women who received both tests within a six-month interval. Of these paired screens, about half (48%) provided discordant results (one normal and one abnormal), indicating that cervical disease does not predict anal disease, or vice versa. Women with normal cervical Pap results had abnormalities in the anal Pap smear in 36% of cases. A comparison of anal Pap smear and biopsy results found that the anal Pap test had a sensitivity of 94.7%, justifying more research using this important screening tool in women.
The study authors suggested that the high level of discordance in this small cohort illustrates that anal and cervical Pap smears provide independent information and that using both in routine evaluations of HIV positive women should be examined further.
As the life expectancy of HIV positive women receiving HAART increases, it has become more important to find markers to identify and prevent cervical disorders -- a necessary adjunct to improved screening tools (see previous item). Previous studies have not reached a consensus on the ability of HPV viral load to serve as a marker for cervical disease.
An Italian study reported in the February 1, 2005 issue of Clinical Infectious Diseases found that HIV positive women with high-grade cervical lesions have significantly higher levels of HPV in their cervix than women at high risk for HPV with no signs of cervical disease.
Flavia Lillo, MD, and colleagues analyzed 64 samples from 16 HIV positive women who had surgery to remove cervical squamous intraepithelial lesions (SIL; abnormal cell growth). These samples were compared with 44 control samples from 22 HIV positive women who were at high risk for HPV but had no signs of cervical disease. The authors reported that all women with SIL had higher HPV viral loads than those in the control group. Additionally, HPV viral loads in the women with cervical disease decreased notably after removal of the damaged tissue. This study suggests that measuring HPV viral load in the cervix could be a clinical biomarker to identify women at risk for the development of cervical cancer.
The researchers did not find a difference between the two groups in the number or subtype of HPV strains detected in the cervix. This allowed them to conclude that measurement of single-strain HPV viral loads, which is impractical in clinical practice due to cost, may be unnecessary in predicting cervical disease risk.
In related news, researchers reported in the April 20, 2005 issue of the Journal of the National Cancer Institute that HPV is more likely to be reactivated in HIV positive women with advanced immunosuppression. Howard Strickler, MD, from the Albert Einstein College of Medicine and colleagues studied 1,848 HIV positive and 514 HIV negative women enrolled in the WIHS cohort. The women received cervical Pap smears and HPV viral load tests every six months for an average of seven years of follow-up (a total of 5,661 person-years).
The researchers found that CD4 cell count and HIV viral load were strongly associated with detectable HPV. A majority of the women had detectable HPV viral loads at some point during the study period. However, women with more advanced HIV disease (CD4 cell counts below 200 cells/mm3 or HIV viral loads above 100,000 copies/mL) were more likely than women with minimal immunosuppression to have subsequent HPV outbreaks after a period of undetectability. Women with more advanced immune suppression were also more likely to develop SIL.
In the cohort as a whole, the incidence of HPV infection was strongly associated with the number of recent sexual partners; however, 22% of sexually inactive HIV positive women with fewer than 200 cells/mm3 still developed detectable HPV after being undetectable, suggesting HPV reactivation rather than new infection. The researchers concluded that more frequent HPV reactivation could help explain the high rates of HPV infection seen in HIV positive women.
A substantial proportion of U.S. women with HIV stop antiretroviral treatment within five years, according to an article in the April 1, 2005 issue of JAIDS. Linda Ahdieh-Grant, PhD, from Johns Hopkins University and colleagues looked at factors associated with HAART discontinuation among 936 HIV positive women in the WIHS cohort who started treatment between 1995 and 2000. Women were divided into three groups based on the date of HAART initiation: October 1995-March 1998, April 1998 - June 1999, and July 1999 - September 2000. All subjects received HAART for at least six months.
The researchers found that nearly one-quarter of the women (24%) discontinued therapy five years or less after they started. Women who had high HIV viral loads and those who experienced small increases in their CD4 cell counts (both potential indicators of treatment failure) were more likely to discontinue therapy than those with undetectable viral loads and larger CD4 cell increases. Depression was also linked to early HAART discontinuation. African American and Latina women were more likely than "white" women to stop treatment during the earlier study periods, but not during the third period.
The rate of treatment discontinuation was higher among women who started therapy during the July 1999 - September 2000 period, reflecting "ongoing and dynamic shifts in the approach to HAART utilization" -- including a greater recognition of the long-term side effects of antiretroviral drugs. (Previous research has shown that women are significantly more likely than men to stop antiretroviral therapy due to adverse side effects.) The authors suggested that their findings "emphasize that access to treatment for depression may have important implications for the management of HIV-infected individuals on antiretroviral therapy."
In March Bristol-Myers Squibb announced that the pregnancy risk category for efavirenz (Sustiva, Stocrin) has been changed from C to D. Category C indicates that the risk of fetal harm cannot be ruled out based on available evidence, while category D denotes actual evidence of fetal risk. The change came about as a result of four case reports of neural tube defects (meningomyelocele and Dandy-Walker syndrome) in infants born to women who took efavirenz during the first trimester of pregnancy. Brain and eye malformations have also been seen in studies of the drug in monkeys. The latest U.S. federal HIV treatment guidelines recommend that women not take efavirenz during the first trimester; use later in pregnancy may be considered if there are no alternatives available and the benefits outweigh the risks. Women of childbearing potential should receive a pregnancy test before starting efavirenz and use effective contraception while taking the medication. Complete efavirenz prescribing information is available at www.sustiva.com.
The use of a single dose of nevirapine (Viramune) to prevent mother-to-child transmission (MTCT) of HIV was thrust back into the spotlight late last year when a National Institutes of Health (NIH) whistleblower questioned how the HIVNET012 trial was conducted. This trial, which began in Uganda in 1997, was the first to show that single-dose nevirapine given to the mother during labor and to the baby within three days of birth was effective at reducing HIV transmission. The MTCT rate after 12 months in breast-feeding women was 16% in women who received single-dose nevirapine compared with rates upwards of 25% in women who received no prophylaxis.
This finding was an important advance because a single dose of nevirapine is relatively cheap and easy to administer throughout the developing world, where the more intensive AZT-based MTCT regimen used in developing countries is not widely available. As such, news stories about the whistleblower's claims that HIVNET012 researchers failed to report safety issues reverberated in many countries where single-dose nevirapine is the basis of MTCT programs.
The NIH maintained that "remonitoring reports of HIVNET012 found no additional serious adverse reactions related to nevirapine," although reviews of the study did reveal problems with record-keeping that the agency said had "no bearing" on nevirapine's safety or efficacy. A report by the National Academy of Sciences Institute of Medicine (IOM) released on April 7 stated that an independent IOM review panel found no major flaws in the study that would cast doubt on the conclusion that single-dose nevirapine is safe and effective in preventing MTCT of HIV. Despite some procedural "shortcomings," said IOM panel chair James Ware from the Harvard School of Public Health, the HIVNET012 findings remain "sound and reliable." Nevertheless, the ethics of using nevirapine in developing countries -- where women with HIV may have severely limited access to both medications and high standards of care -- remains controversial.
More Resistance in Mothers Following Single-Dose Nevirapine
At the 2005 Retrovirus conference, seasoned MTCT researcher James McIntyre, MD, of the University of Witwatersrand in Johannesburg presented a summary of nevirapine's role in preventing MTCT. McIntyre dismissed doubts about nevirapine's safety based on evidence in thousands of women and babies that have been studied in MTCT trials to date. However, he also emphasized that researchers have accumulated new knowledge about better ways to prevent MTCT of HIV without jeopardizing future treatment options for women. Several oral presentations and posters at the meeting highlighted the potential for women to develop resistance to the entire class of nonnucleoside reverse transcriptase inhibitors (NNRTIs) after receiving only one dose of nevirapine during childbirth.
Single-dose nevirapine for the prevention of MTCT was previously associated with the development of NNRTI resistance in 30% to 50% of women. Now, researchers are finding that resistance appears to be even more common. In an oral presentation at the same conference (abstract 100), Jeffrey Johnson from the U.S. Centers for Disease Control and Prevention (CDC) reported that a majority of pregnant women who receive single-dose nevirapine develop resistance.
In this study, investigators conducted genotypic resistance tests on plasma samples -- taken both before and after receiving nevirapine -- from 50 women who were part of a South African MTCT study. The analyses were performed using a highly sensitive assay that could detect resistance at levels as low as 0.2% for the K103N signature nevirapine-resistance mutation. Traditional assays require that the resistant variant make up at least 20% of the total virus population. Using the more sensitive method, an additional 16 women who were previously thought to have no resistance were found to have the K103N mutation. This finding suggests that conventional resistance assays identify only a portion of the women who develop resistance after single-dose nevirapine.
In another oral presentation at the Retrovirus conference (abstract 101), Sarah Palmer, PhD, of the National Cancer Institute reported on the persistence of resistance mutations following single-dose nevirapine in South African women. The first group of eight women in this study had evidence of NNRTI resistance at six weeks and at six months, but not at one year when resistance was measured using traditional genotypic tests. However, using a more sensitive resistance assay, the researchers found that seven of these women (88%) still had resistance mutations one year after taking single-dose nevirapine. In a second group of nine women, the sensitive assay detected mutations in seven women (78%) who were previously found to have no resistance at six months using standard tests.
Palmer and colleagues concluded that populations of drug-resistant HIV variants following administration of single-dose nevirapine may decline over time, but can persist for up to one year after receiving the drug. These results suggest that, whenever possible, pregnant women should receive combination antiretroviral therapy rather than nevirapine monotherapy.
Single-Dose Nevirapine Prevents MTCT in Second Pregnancies
The first study to analyze the efficacy of single-dose nevirapine in preventing MTCT during second pregnancies was presented at the February Retrovirus conference by Neil Martinson, MBBCh, MPH, of Johns Hopkins University (abstract 103). The study enrolled participants from 13 prenatal clinics in Soweto. Data were obtained from 77 mothers who had previously received single-dose nevirapine and 140 mothers without past nevirapine exposure as controls; results from additional subjects were not available for presentation but are expected in the future.
A preliminary analysis found that eight of 77 nevirapine-experienced women (10.4%) who took the drug again during a second pregnancy transmitted HIV to their babies, compared with five of 140 women (3.6%) receiving nevirapine for the first time. While the difference between the two groups may appear large, it was not statistically significant because the study included too few participants (that is, it did not have sufficient power) to rule out the possibility that the difference was due to chance (see "A Guide to Clinical Trials" in this issue). The study team noted that the 10.4% transmission rate in the group receiving a second single dose of nevirapine was comparable to rates seen in previous studies of women receiving the drug during first pregnancies.
Researchers had suspected that resistance mutations might limit the effectiveness of nevirapine in preventing HIV transmission in subsequent pregnancies. Although the results were inconclusive, this study supports the use of single-dose nevirapine in multiple pregnancies because transmission rates were lower than rates seen in women who receive no prophylaxis.
Kristen Jill Kresge is a freelance writer and editor based in New York City.
Liz Highleyman contributed to this article.
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This article was provided by San Francisco AIDS Foundation. It is a part of the publication Bulletin of Experimental Treatments for AIDS. Visit San Francisco AIDS Foundation's Web site to find out more about their activities, publications and services.