Delivering on Women’s Health Issues

Hopkins HIV Report 2006 Sep; 18(5):6-9

Jean R. Anderson, M.D. and Barbara Wilgus-Wegweiser, C.R.N.P.
Johns Hopkins

The XVI International AIDS Conference will be remembered as the first to provide a strong focus on HIV infection in women. Although there were relatively few new data presented scientifically in terms of issues specifically related to women with HIV, the feminization of the HIV/AIDS epidemic, and the gender inequities that continue to drive it were acknowledged, discussed and debated in (conservatively) some 400 abstracts, 1 plenary session, 2 symposia, 1 special session, 7 skills building sessions and 13 satellite sessions, not to mention by most of the speakers in the opening ceremony. Almost 3000 abstracts contained the words women or gender.

The following summary represents a selection of these presentations that were chosen by the reviewers for their relevance to clinical care and scientific interest.

HIV Prevention

Measures to prevent the spread of HIV infection were a key focus of the conference and continue to be a challenge. The controversy of so-called “ABC” (Abstinence, Be faithful, use Condoms) behavioral interventions continues to be an issue, with many presentations alluding to the failure of this measure in stemming the spread of HIV. Pulerwitz presented information regarding one such program in Kenya, where questionnaires given to 1300 adults and youth ages 13 to 19 asked for specific definitions of each ABC category [Int Conf AIDS. 2006 Aug 13-18;16:Abstract No. MOAX0503]. The investigators found limited awareness of what the ABC terms mean: 39% of adults and 46% of youth were able to correctly define abstinence, 35% of adults and 23% of youth correctly defined being faithful, and only 17% of adults and 13% of youth correctly defined preventive condom use. The questionnaire also asked participants to identify their primary source of health care information, which in the case of this cohort was the radio, though most respondents expressed a preference for health care information to come from health care providers.

Vaginal microbicides and their potential as a prevention measure for women were a topic of excitement at this conference and were discussed in several sessions. The key research goals at this time are to match vaginal microbicides to transmission mechanisms, blocking viral attachment with barrier, chemical, and even antiretroviral measures. Clinical effectiveness data are still forthcoming, however, with the first large-scale clinical trial data expected in 2007 and at this conference information was limited to development data [Shattock R, Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. WEAA0501].

Finally, HSV suppressive therapy as a means of decreasing genital HIV RNA shedding has been studied in several small clinical trials. Mayaud presented data from the ANRS 1285 trials in Burkina Faso [Int Conf AIDS. 2006 Aug 13-18;16:Abstract No. TUAC0501]. These are randomized controlled trials studying the effect of valacyclovir (VCV) 500 mg bid versus placebo with (ANRS 1285B) or without (ANRS 1285A) HAART on genital HIV RNA, genital HSV-2 DNA, and plasma HIV RNA among HIV/HSV-coinfected women. Over a 75-day pre-treatment period, 140 women in 1285A and 60 women in 1285B underwent biweekly virologic measurements and were then randomized to treatment versus placebo for up to 165 days. In the 1285A group not on HAART, both the frequency and quantity of genital HIV RNA shedding were significantly reduced by VCV, with a 20% decrease in quantitative genital HIV RNA from one biweekly measurement to the next (p<0.01). The 1285B group on HAART, however, did not show a significant reduction in detectable genital HIV RNA (36.7% vs 40.0%, p=0.79) beyond levels achieved by HAART. Both 1285A and 1285B are limited by a small sample size. Further investigation with larger clinical trials is warranted to determine whether HSV suppressive therapy will be effective as a prevention method.

HIV in Pregnancy

HIV Acquisition in Pregnancy. Recent published studies suggest that pregnancy may be a time of unique vulnerability to HIV acquisition, even when controlling for sexual behavior [Gray RH, et al. Lancet. 2005 Oct 1;366(9492):1182-8]. Two large studies appear to contradict this conclusion. Urassa and coworkers utilized demographic surveys and village HIV testing in Tanzanian women of childbearing age from 1994-2005. Analyzing 17,928 person-years of observation and 5755 pregnancies, the investigators found that successful pregnancy was associated with lower HIV incidence (relative risk 0.3, CI 0.2-0.4) [Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. MOPE0324]. Although it was not possible to determine whether seroconversion actually coincided with pregnancy, the strength and consistency of the findings, even after adjustment for possible confounders, supports the conclusion that pregnancy is associated with decreased HIV incidence. Similarly, a prospective study conducted in Uganda and Zimbabwe involving 4,439 women 18-35 years and 31,369 follow-up visits, found that neither pregnancy nor lactation placed women at increased risk of HIV seroconversion [Morrison C, et al. Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. MOPE0346].

HAART in Pregnancy. The use of effective combination antiretroviral therapy regimens in pregnancy has become the standard of care and the mainstay in preventing mother-to-child transmission in resource rich countries. However, concerns remain about potential toxicity or adverse effects of these regimens, particularly among women who do not yet require ART for treatment of their own HIV infection.

Using comprehensive population-based surveillance in the UK and Ireland from 1990-2005, Townsend and coworkers studied the effect of antiretroviral therapy on preterm delivery [Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. MOPE0532]. Analyzing approximately 5,000 pregnancies, the authors found that the risk of preterm delivery (<37 weeks) was increased 1.5-fold with exposure to HAART compared to mono- or dual-therapy exposure, after adjustment for age, ethnicity, clinical status and IDU risk factor (adjusted OR 1.5, 95% CI 1.2-1.9, p=0.001). This association was found with both PI- and NNRTI-based HAART. This confirms previous reports from Europe, but, as the authors note, must be balanced against the substantial benefits of HAART in reducing perinatal transmission.

There has been equivocal evidence concerning in utero NRTI exposure and mitochondrial toxicity in HIV-uninfected infants. A retrospective review of 1,020 HIV-uninfected infants born to HIV-infected mothers in PACTG protocols identified 20 possible cases of mitochondrial dysfunction using standardized criteria. There was no significant association between in utero NRTI exposure any time in gestation and clinically evident mitochondrial toxicity [Brogly S, et al. Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. THAB0103].

An ongoing concern about the use of HAART for perinatal prophylaxis is the risk of antiretroviral drug resistance development, potentially affecting response to future regimens used for treatment. Duran and colleagues analyzed the occurrence of primary resistance mutations in a prospective cohort of 198 women in Latin America and the Caribbean who were newly diagnosed with HIV and first exposed to antiretroviral drugs during pregnancy [Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. WEAB0103]. Genotypic resistance testing was performed at baseline and at 6-12 weeks postpartum. At baseline 98% of women were asymptomatic and 62% had viral loads <1,000 c/mL. When taking into account the inability to amplify samples (generally due to very low viral load), primary resistance mutations were detected in 9/76 (12%) at enrollment and 12/97(12%) at 6-12 weeks postpartum. Detection of resistance was not associated with plasma viral load, CD4 cell count, CDC disease stage, timing of antiretroviral drug exposure, or the complexity or number of regimens. The occurrence of resistance was not associated with perinatal transmission nor with the short-term use of HAART for prophylaxis, and the rate of resistance mutations was similar to that reported among other newly HIV-diagnosed individuals in the region. These findings reinforce the recent change in USPHS Perinatal Guidelines recommending resistance testing prior to initiation of therapy or prophylaxis in pregnancy. The most common PI used in HAART regimens during pregnancy in the US, and listed as a preferred PI in the USPHS guidelines, is nelfinavir (NFV), because of its safety profile, tolerability and availability of PK data. However, studies in non-pregnant adults have demonstrated that NFV is inferior virologically to more potent ritonavir (RTV)-boosted PIs such as lopinavir/ritonavir. The question remains whether NFV can be used without detriment in women who need treatment only for prevention of mother-to-child-transmission (PMTCT), with plans to discontinue therapy after delivery. Kakehasi presented the first data trying to address this issue [Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. WEAB0105]. New NFV-associated mutations developed in 5/19 (26.1%) women exposed to NFV for prophylaxis only, 2 of which were major. There was no association with HIV subtype (70% were subtype B). Although this study provides useful and potentially concerning information, it is limited by small numbers and lack of information with respect to dosing/formulation, adherence, pharmaco-kinetics and associated nutritional intake. Further study is clearly needed.

Continued analysis by the Antiretroviral Pregnancy Registry, now updated through July 2005 with 5,169 live births, found 1,980 first trimester exposures to ARV drugs with a total of 59 (3.0%) birth defects, which is not different from the general US prevalence (3.1/100 live births) based from CDC surveillance statistics [Beckerman K, et al. Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. MOPE0515].

Prevention of Postpartum Infectious Complications. The use of prophylactic intrapartum antibiotics is routine for Cesarean deliveries in HIV-infected women to prevent postpartum infections. Sebitloane and colleagues conducted a double-blind randomized clinical trial of a single 2 gm dose of cefoxitin for prevention of septic complications in 675 HIV-infected women in whom delivery was anticipated [Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. WEPE0241]. Overall, septic complications were reduced from 40.6% to 18.9% by use of antibiotics in women with CD4 counts <200 cells/mm³ (p=0.005); in the study sample infections were reduced by 22%, although this was not statistically significant. Most infections were diagnosed by 1 week after delivery and were associated with episiotomies. Missed Opportunities. Availability of effective combination ARV therapy in pregnancy and safe and affordable alternatives to breastfeeding have resulted in perinatal transmission rates of less than 2% in developed countries. “Opt-out” HIV testing, in which patients are tested routinely unless they refuse testing, has been recommended in pregnant women in the US for some time in order to take advantage of these interventions, although this approach is still not universally applied and is not legal in Maryland given current statutory restrictions. The American College of Obstetrics and Gynecology also recommends repeat HIV testing in the third trimester in selected high risk women. Two studies confirm that women who seroconvert during pregnancy are responsible for a significant proportion of the remaining perinatal transmissions occurring in the US. In an analysis of 2144 HIV seropositive birth events, Birkhead and colleagues found that only 1.4% represented seroconversions (tested HIV-negative early in pregnancy), yet these accounted for 23.4% of all MTCT in 2002-2004 [Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. WEPE0271]. Similarly, the CDC analyzed data from women who were initially HIV-negative in pregnancy and either tested positive within 3 months of delivery or had an infant who tested positive at delivery or by two years of age if not breastfed [Sansom S, et al. Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. WEPE0269]. The authors found that among 4,006 deliveries by HIV-infected women, 1.4% had seroconverted during pregnancy; these accounted for 8.2% of all transmissions in this group, with a significantly higher rate of transmission (29.3%) than in those who had not seroconverted (4.8%).

Pregnancy in Low Resource Settings. Over the past 6 years there has been a new commitment to HIV interventions, most prominently PMTCT in low resource settings where the majority of infections continue to occur. Although overall goals have not been met, it is clear that there is much to celebrate. Spensley reported on the experience of the Elizabeth Glaser Pediatric AIDS Foundation in 11 countries with HIV prevalence of at least 6%, where PMTCT programs have expanded and reached over 1.3 million women [Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. TUPE0338]. In the DREAM cohort in Mozambique, in which HIV-infected women were offered HAART irrespective of CD4 count beginning at 25 weeks gestation through 6 months postpartum and all women breastfed, the MTCT rate was 1.2% at 1 month of age in 171 mother-infant pairs [Marazzi MC, et al. Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. WEPE0545].

Because nevirapine (NVP)-based HAART or use of single-dose NVP is generally the standard for pregnant women in low resource settings, there are serious concerns about the development of NVP resistance, particularly among women who are treated prophylactically and do not continue effective therapy after delivery. There is a particular concern with NVP both because of its long half-life and its low genetic barrier to resistance. Two studies addressed this issue. Jourdain and colleagues studied 24-month outcomes of NVP-based HAART in postpartum women who had participated in perinatal HIV prevention trials utilizing single-dose (SD)-NVP [Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. WEAB0102]. A total of 286 women with a median CD4 count of 154 cells/mm³ initiated HAART a median of 7.7 months after delivery. In an intent-to-treat analysis (switch=failure) at 2 years, 55% had a viral load <400 c/mL. Although the same group had demonstrated that exposure to SD-NVP reduced the likelihood of maximal viral load suppression at 6 months after initiating HAART, this was not seen at 24 months, although the power to detect a significant difference at this time period was low. Chi reported on a study of 6100 women in Zambia who initiated NVP-based HAART, of whom 679 had been exposed to SD-NVP in pregnancy (median 16.1 months prior to initiation) [Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. WEAB0104]. Looking at CD4 response and clinical outcomes but not viral load suppression, there was no difference in CD4 response at 6 and 12 months and mortality trends were similar. Of significance, those women unexposed to SD-NVP were older and had more advanced disease at baseline. Both of these studies may be considered mildly reassuring but are still far from definitive. This is an issue of considerable importance, and more studies with longer follow- up, larger sample sizes, and more sensitive measures of virologic failure are urgently needed.

There are also continued cautions about the use of ongoing NVP-based regimens due to hepatic toxicity. In Mozambique, mild-moderate and severe hepatic toxicity was reported in 29% and 3% respectively of 254 pregnant women on NVP-containing regimens; the rate of severe hepatic toxicity was doubled in women with CD4 counts 250-350 cells/mm³ [Jamisse L, et al. Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. WEPE0173]. In Malawi 3 serious rashes and one case of clinical hepatitis were seen among 39 postpartum women (all with CD4 counts >200 cells/mm³) exposed to 28 days of ZDV/3TC/NVP as a PMTCT intervention during breastfeeding [Bramson B, et al. Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. WEPE0082). No similar complications were seen in women exposed to NFV-based regimens or to no therapy.

Fertility Intentions in HIV Positive Women and Men

Several studies assessed fertility intentions in both HIV seropositive women and men. Hoffman and coworkers enrolled 227 Malawian women in a longitudinal cohort at the time of first HIV-positive test and assessed pregnancy status, fertility intention, and contraceptive use quarterly for 1 year [Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. WEAC0103] While the desire to have another child decreased significantly over the first year after HIV diagnosis (35% to 13%, p<0.0001), neither use of contraceptives (38% to 49%) nor use of condoms (4% to 5%) changed significantly, indicating a serious disconnect between desire for pregnancy and actions toward preventing pregnancy. Sixteen women became pregnant in the first 6 months of the study and an additional 13 in months 6-12 for an overall incidence of 15.5/100 person-years; pregnancy incidence was 12.8/100 person-years among women who did not want pregnancy versus 32.0/100 person- years in those who expressed a desire for pregnancy (p<0.02). Paiva and associates assessed the fertility intentions of 729 HIV-infected women and 250 HIV-infected bisexual or heterosexual men in Brazil using both a questionnaire and face-to-face interview [Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. TUAD0105]. Of the respondents 89% were on antiretroviral therapy and 28% expressed a desire to have more children. When analyzed by sex, the proportion of men desiring children was 50% compared to 19% of the women; this was the most significant variable. However, men had significantly less knowledge about MTCT than women. In Brooklyn, New York, 30 HIV-infected men were questioned regarding fertility intentions in a pilot study conducted from October 2003 to January 2004 [Weinberg A, et al. Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. TUAD0101]. Regardless of fertility intentions, 87% of respondents reported that they had not discussed family planning with their health care provider at any visit, and 50% said they wished to discuss this issue. This pilot study did not include female respondents for comparison. These studies emphasize the need to address fertility intentions in both HIV+ women and men and to improve male involvement in reproductive health care.

HPV and Cervical Dysplasia

Cervical dysplasia and cervical cancer remain a significant factor in morbidity and mortality in HIV-infected women worldwide. There is limited screening and treatment for cervical dysplasia in developing countries, which has been extensively noted in the literature, but HPV type specific testing adds new considerations for potential clinical management. Parham and collaborators evaluated prevalence and predictors of cervical cytological abnormalities among 150 HIV-positive women in Zambia and were able to incorporate HPV type-specific testing into their study [Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. TUAB0303]. The prevalence of cytologic abnormalities in this cohort was 76% (114/150), with high-grade squamous intraepithelial lesion (SIL) in 33% (49/150) and with suspicion for carcinoma in 20% (30/150). High-risk HPV types were found in 85% of women (128/150), and multivariable logistic regression modeling suggested that this was an independent predictor for severely abnormal cytology (adjusted OR 12.4, p<0.02). Interestingly, type-specific testing showed that HPV type 52 was the most prevalent type in this cohort, with type 58 the second most prevalent. HPV types 16 and 18, which are the types targeted in the newly FDA-approved preventive HPV vaccine and in therapeutic HPV vaccine trials, were far less prevalent in this cohort, ranking 9th and 16th respectively. This correlates with the findings of Luque and associates, who also found that HPV types 52 and 58, not 16 or 18, were most prevalent among 229 HIV-positive women in Rochester, New York with high grade cervical SIL [J Infect Dis. 2006 Aug 15;194(4):428-34]. Studies such as these are important and may have implications for vaccine administration in HIV-infected women, who have not been included in vaccine trials to date; studies of vaccine effectiveness in immunocompromised populations are planned.

Miscellaneous Issues in Women

Finally, three studies remind us that HIV- infected women may be especially prone to certain psychosocial and societal ills that may significantly affect clinical management and adherence, that much work remains to be done to support the prevention needs of women and the failure of the ABC approach. In a comparison of 629 women in the WIHS study and 1,829 men in the MACS, both large multi-center US cohort studies, women had a higher proportion of deaths due to accidents or injuries (7.3% vs 2.8%) [Cohen M, et al. Abstract WEAX0305]. Two-thirds of the deaths in women were attributed to drug overdose, poisoning or suffocation compared to less than 1/3 in the men. In the multivariate analysis, independent variables associated with mortality included being in the WIHS, unemployment, depression and injection drug use. In another study of 344 HIV-infected and 133 HIV-uninfected women from the WIHS, having HIV infection was associated with greater anxiety and feelings of hopelessness, with a positive association between feeling hopeless and suicidal ideation [Schwartz R, et al. Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. THPE0612]. The final study comes from WHO and uses population data from 2000-2003 to assess the prevalence of physical and sexual violence against women in 15 sites in 10 countries, primarily in Africa, Asia, and South America [Watts C, et al. Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. THPE0692]. Depending on site, a coerced first sexual experience was reported by 0.4-30% of women, and 9-59% reported sexual violence since the age of 15 (in 9 the sites prevalence was >30%). Of women who had ever been in a sexual partnership, 6-56% reported sexual partner violence, which was strongly associated with knowledge of the man’s unfaithfulness.

Summary

The XVI international AIDS Conference focused on several issues of importance for women with HIV infection. Presentations on prevention continue to highlight the challenges of risk reduction strategies in a world where women are often without power, while simultaneously offering the hope that new technologies such as microbicides will give women an opportunity for HIV prevention not dependent on the behaviors of their partners. Prevention of mother-to-child-transmission continues to be a major issue, as in previous conferences, and in the era of scale-up of PMTCT services, more studies will be needed regarding adverse events and resistance following HAART therapy in this setting. Fertility intentions of both women and men with HIV were shown to be a significant issue and one that should not be overlooked by health care providers, as there is often a disconnect between intentions and prevention behaviors. HPV type-specific testing provided new insights into cervical dysplasia, and in the era of vaccine development may have future implications for HIV-infected women. Finally, psychosocial and societal factors affecting women’s HIV care remain a worldwide concern, both for treatment and prevention, and must continue to be addressed.

2006-09-10
HHR-2006-09-03

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