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Retroconference Update: HIV and Women
Written for NATAP by Judith Aberg, MD, Washington University, St Louis, MO, ACTG
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Although there remains much interest among researchers and pharmaceutical companies to address issues related to women, we have yet to see much initiative in this area. There were few clinical trials that had sufficient enrollment of women to address women related virologic/immunologic responses or complications to therapy. Similar to last year, the last rows of the posters were devoted to women and children with HIV including prevention and HIV transmission. In fact the very back row was the "Sex/Gender and HIV-1 Disease Outcomes". Each day I walked through and there were few conference attendees who made it all the way to the back. One of my colleagues asked if there was anything worthwhile back there? Enough said. There was a symposium on February 12 in which 4 speakers discussed various aspects of the impact on HIV among women.
The first speaker was Dr. Suniti Solomon, from the YRG Center for AIDS Research and Education, Madras, India, who discussed the deplorable conditions for women infected with HIV living in India. This is a culture where infanticide may occur if a woman gives birth to a female infant instead of a male. Women may be forced to practice unprotected sex with an infected spouse in order to reproduce. If she does not have children, she is often cast aside. Every 34 minutes a woman is raped, every 42 minutes a woman is a victim of domestic violence and every 93 minutes a woman is burnt to death over dowry. 47% of new HIV infections occur in women with 60% among 15-29 years of age. Among women with HIV, the mean age is 29 years, 95% are married, 81% are housewives and 88% reported monogamy. In a study addressing the use of microbicides, 68% of men had more than 1 partner compared with 6% of females. 95% of female sex workers (FSW) and 72% of housewives said they would be willing to use microbicides. Indian men, on the other hand are more willing to use preventive measure with a mistress or FSW or allow those women to use preventive measures than their wives. 58% of men said they would not allow their wife to use a micobicide compared with 10% who said they would not allow a FSW to use one. Another disillusioning comment was the continuation of the myth that a man with a STD can be cured if he has sex with a virgin. Dr. Solomon outlined prevention programs, which she hopes will be implemented to decrease the rising incidence of HIV. She currently estimated that the AIDS case rate was 26/1000 and in some regions the population prevalence was greater than 5% among women of child-bearing years. In a country with an estimated population of over 1 billion, the socio-economic costs are staggering. We all sat there as if we had just been defeated. This is much more than treating a disease. How do you change a culture?
In the USA, HIV remains the number one cause of mortality among women of color age 25-44 years. In striking contrast to Dr. Solomon's talk, Dr. Ruth Greenblatt from University of California, San Francisco presented results from the Women's Interagency HIV Study (WIHS) conducted at several sites in the USA. The WIHS is a longitudinal, observational study of the effects of HIV and related conditions on women. Initial enrollment of 2,658 HIV infected and uninfected women occurred between 1993-1994 at 6 locations in the U.S and additional sites joined in 2000-20001. Interviews, physical examinations, and specimen collection are performed at each biannual study visit. Study evaluations include key medical history events, antiretroviral treatment use, plasma HIV RNA, lymphocyte subsets, cervical and anal cytology, cervical colposcopy, and body habitus measurements. Medical record and registry verification are obtained for key outcomes.
The WIHS HIV seropositive cohort is comprised of 56% African-Americans and 23% Latinos, median age of 36 years with a median CD4+ T-cell count of 330 cells/mm3. The median VL is 22,000 copies/ml. The HIV seronegative cohort is comprised of 54% African-Americans and 28% Latinos with a median age of 34 years. Dr. Greenblatt emphasized that retention in the WIHS cohort has remained over 80%. This is an important note because there have been historic concerns that women do not enroll into clinical trials because of the demands of frequent follow-up. Interestingly, Dr. Greenblatt showed a Cochrane review of 49 randomized clinical trials of ART with a total of 15,612 participnts (12.5% female) and none of the trials had subset analysis for outcomes among women. Dr. Greenblatt's point is that many trials exclude women and that the WIHS is an example of women willing to enroll and actively participating for years. She looked at one particular salvage ART study and then looked at the 1280 women enrolled in WIHS that were on ART to determine if they would have been eligible for this salvage study. 81% of the women enrolled in WIHS would be excluded for one reason or another. She then reviewed sex differences regarding viral load and noted that in most studies, the baseline VL is lower among women compared with male participants of the MACS study when stratified by CD4 cell count and that VL varies with the ovulatory cycle. Sex differences may play a key component in the immune system development and responses and even at the molecular level such as regulation of viral entry receptors and fusion. Dr. Greenblatt gave several examples of how progesterone may alter cell physiology and cytokine expression. Many subset analyses of this cohort will provide valuable information over time on such women related issues such as lipoatrophy, lipohypertrophy, cervical pathology, and prevalence/consequence of human papilloma virus. Special attention to the medical and social needs of this patient population are indicated and further studies enrolling significant proportions of women are greatly warranted.
Vitamin A Deficiency
Dr. Jared Baeten discussed the possible influence of Vitamin A and hormone contraceptive use on HIV transmission and disease progression among women. Vitamin A deficiency and hormonal contraceptive use are common among women in developing countries, and studies have suggested that both factors may influence the natural history of HIV-1. Since 1993, Dr. Baeten and colleagues from the University of Washington, Seattle have conducted studies of HIV-1 infectivity and natural history among HIV-1 infected and at-risk women in Mombasa, Kenya. Vitamin A deficiency has been associated with lower CD4+T-cell counts, faster disease progression, increased mortality, increased HIV-1 genital shedding and increased maternal to fetal transmission. The question is whether this is a cause and effect or whether Vitamin A deficiency is just a marker for advanced disease. Therefore, the group sought out to determine if Vitamin A supplementation would result in improved CD4 counts, lower HIV Vland decreased HIV-1 vaginal shedding. The role of vitamin A deficiency in HIV-1 disease was assessed in a placebo-controlled randomized clinical trial of daily oral vitamin A supplementation among 400 HIV-1 seropositive women for 6 weeks. The median age was 28 years with a median CD4 226 (range <25-1117) and 59% had Vitamin A deficiency. 354 (89%) women returned for follow-up and 95% adherence of study drug was reported for 96% of the particpants. There was no significant difference in the prevalence of HIV-1 DNA (18% vs 21%, p = 0.4) or the quantity of HIV-1 RNA (3.12 vs 3.00 log10 copies/swab, p = 1.0) in vaginal secretions of women receiving vitamin A compared to women receiving placebo, and no effect of supplementation on plasma HIV-1 viral load or CD4 counts was observed. Vitamin A supplementation is unlikely to decrease the infectivity of women infected with HIV-1 or impact disease progression and most likely represents a consequence of advanced disease.
Oral Hormonal Contraceptive (DMPA) Increased Risk for HIV-Infection
Dr. Baeten and colleagues also examined the effect of hormonal contraceptive use on the risk of HIV-1 acquisition and subsequent disease progression in a prospective cohort study of 1498 HIV seronegative FSW. The cohort had monthly visits which included STD/HIV screening and risk reduction counseling. The median age was 26 years. Frequency of sex was twice weekly (range 0-13) with one partner (range 0-10) and they reported "median" 100% condom use (range 0-100), <1% anal sex and no IVDU. Approximately 250 women became infected with HIV-1 and whose date of infection could be accurately estimated were followed for a median of 34 months after the time of HIV infection. This high number makes you question the accuracy of the risk exposure the FSWs reported and therefore, the clinical value of such a study. The use of oral contraceptive pills and the injectable contraceptive depot medroxyprogesterone acetate (DMPA) was associated with increased risk of HIV-1 acquisition. (OR 2.4, 3.0; respectively). Among women who became infected with HIV-1, DMPA use at time of infection was associated with higher set point plasma viral load (+ 0.33 log10 copies/ml, p = 0.03). Multiple viral variants were detected in 57% of these women and were more common among those who used hormonal contraception at the time of HIV-1 acquisition (OR 2.7, p = 0.003). Viral diversity was associated with more rapid CD4 decline. The use of hormonal contraception may be associated with increased risk of HIV-1 infection, acquisition of a more complex virus population, higher HIV-1 plasma viral load, and faster disease progression. Further studies are needed to explore this finding.
Differences Between Men & Women in HIV Therapy: more studies STILL needed
Dr. Kathleen Squires from University of Southern California presented an excellent overview on the impact of sex differences on ART and its complications. Her first point was clear and simple- women will participate in clinical trials so get out there and recruit them! She reviewed the Women First Trial, which showed that the 48 week HIV VL and CD4 response on PI/NRTI regimen was similar to that of other trials enrolling predominantly men. For the most part, ART clinical trials and cohort studies have not seen an appreciable difference in outcomes (CD4 counts, VL and time to suppression or failure) between men and women. Nevertheless, many of these trials have inadequate numbers of women enrolled for detection of clinically significant differences. Dr. Squires referenced abstract # 926 by Dr T Foutes and colleagues from Ontario. They investigated virologic and immunologic responses to ART among men and women enrolled in a prospective longitudinal database. Of the 470 participants, 60 (12.8%) were female. Women had higher baseline CD4 counts (median 315 vs 272 calls/mm3) and lower baseline VL (median 16,887 vs 33,185 copies/ml) compared with men. Although there was no significant difference between time to virologic suppression, there was a significant difference in time to VL rebound (median time 17.2 months for women compared with 51.8 months for men). How much of this was secondary to difficulties in adherence due to toxicities or other reasons is unknown. Of interest, women did experience a greater increase in CD4 counts (471 vs 289 cells/mm3). In contrast, Dr. P. Keiser and colleagues (abstract # 927) compared treatment outcome among 162 ART-naive women vs 324 ART-naive men starting a nelfinavir-containing regimen. Time to virologic failure was longer in women (295 days) compared to men (236 days). The percent of patients achieving an undetectable VL (<400 copies/ml) was greater in females than males (48% vs 34% at 1 year, 36% vs 25% at 2 years). They also looked at baseline weight as a predictor and did note that there was an increased risk of virologic failure associated with increased weight (>180 lbs, OR 1.4) suggesting that possibly women did better in this study due to lower body weight and having higher levels of nelfinavir.
Both these abstracts emphasize the need for further studies to explore whether there are significant differences among sexes in virologic suppression and durability of ART. Dr Squires asked to what extent does pharmacokinetics, pharmacodynamics, tolerability, side effect profile, hormones and pregnancy play a role in these differences. She then proceeded to give examples of how these factors play a role but most importantly to demonstrate how little we actually know about them. In one indinavir therapeutic drug monitoring (TDM) study, 9.7% of women required a dose reduction compared to 1.1% of men to avoid toxic side effects. Several studies suggested that lower body weight was associated with increased side effects and intolerance presumably via higher drug levels. Yet most of the HIV therapies are not weight dosed. Drug interactions play a major role in toxicity yet little is known about the various hormonal replacement therapies and contraceptives effect on ART.
Dr. Squires then went on to talk about tolerability and complications from therapy. Again, there are few studies addressing the differences but some studies do suggest there is an increase of pancreatitis, hepatic steatosis, lactic acidosis and fat redistribution among women as well as less lipid abnormalities (particularly triglycerides) compared with men. The data on osteopenia and osteoporosis remain uncertain as to whether this is a true HIV related risk or represents more traditional risk factors. Certain acute toxicities such as liver function abnormalities and rash appear more common in women. Dr. Squires had one incorrect reference for a study demonstrating an increased incidence of rash among women on nevirapine compared to men (correct reference is Bersoff-Matcha in Clin Infect Dis 2001). The sex differences are a complex issue given the multiple confounding factors. Frequently, pharmacokinetic trials enroll HIV seronegative men only. As the HIV epidemic continues to grow among women, we need to know if there really are treatment differences in respect to immunologic and virologic responses and the durability of these responses. At any one time, at least 10 percent of HIV-infected women of child bearing age are pregnant, yet little is known about the immunologic and virologic responses during pregnancy, the efficacy of the treatments and the complications from these therapies. Large prospective trials comparing differences are desperately needed.
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