Important note: Information in this article was accurate in May 2002. The state of the art may have changed since the publication date.
Although new information presented about issues relevant to reproductive health and pregnancy in HIV-infected women was sparse at the 9th CROI, there were a few key presentations and a number that add important emphasis to previous observations.
Several presentations addressed factors related to cervicovaginal shedding of HIV, which likely plays an important role in the infectiousness of persons with HIV. Critchlow presented data on 170 women infected with HIV-1 and 51 with HIV-2, comparing plasma and vaginal RNA and DNA viral loads [Abstract 19]. Frequency of detection of vaginal HIV RNA was higher among women infected with HIV-1 compared with HIV-2 (82% vs 59%). Vaginal HIV RNA was highly correlated with plasma HIV RNA. Vaginal HIV RNA could be found in the absence of HIV DNA: HIV-1 RNA was detected in 73% of samples with negative HIV-1 DNA and in 53% of HIV-2 DNA negative samples. Local factors associated with vaginal HIV RNA in both groups included elevated
vaginal pH and genital tract infections, including bacterial vaginosis, tricho-moniasis, HPV, and candidiasis.
In a prospective study of 19 HIV-1 infected and 11 HIV-2 infected Senegalese women followed for up to 6 weeks, vaginal lavage specimens were collected every 3 days [Hawes, Abstract 785-W]. In multivariate analysis after adjusting for plasma HIV RNA, detection of genital HIV was associated with HIV-1 infection (OR=3.2), recent menses (OR=3.2), amenorrhea (OR=6.5), and low CD4 count (OR=5.4 for CD4 <200/mm3). Over a six-week period, 87% of women infected with either HIV-1 or HIV-2 had detectable levels of HIV in vaginal lavage specimens at some time, even in the presence of low plasma HIV RNA levels. However, virus was only detected intermittently in 47% of women.
Cu-Uvin compared two different collection methods to assess HIV in the genital tract. Among 78 women with paired cervicovaginal lavage (CVL) and Sno-Strip cervical samples, Sno-Strip cervical samples clearly outperformed CVL [Abstract 782-W]. Forty percent of Sno-Strip samples had HIV RNA levels greater than plasma viral load, compared with only 7.5% of CVL samples (p<0.001). The Sno-Strip collection technique detected HIV RNA in 22% of samples when CVL was undetectable (<400 c/mL). The findings are thought to be due to the dilutional effect of CVL and/or viral load differences within various genital compartments (the endocervix may be the primary source of HIV in the female genital tract).
Pregnancy and hormonal contraceptive use have been correlated with cervicovaginal shedding of HIV-1 in past studies. Two studies presented at the 9th CROI evaluated additional factors associated with HIV-1 RNA in genital secretions. The relationship between the menstrual cycle and daily genital HIV-1 RNA shedding was examined in a study of 17 women over 1 month and included measurement of luteinizing hormone (LH), estrogen and progesterone throughout the cycle, as well as plasma viral load [Benki, Abstract LB2]. There was an increase of 0.05 log10 HIV RNA c/mL in genital samples over the second half of the cycle beginning with the midcycle LH surge, suggesting that genital viral load
reaches a nadir before ovulation and then increases during the second half or secretory phase of the menstrual cycle. The presence of menses was not associated with increased cervical HIV RNA. Cu-Uvin presented a longitudinal study evaluating factors associated with HIV-1 RNA shedding by CVL in 97 HIV-1 infected women followed over 24 months [Abstract 784-W]. Plasma viral load was significantly associated with CVL HIV-1 RNA, with a three-fold increase in the odds of having detectable HIV in the genital tract for each log10 increase in plasma viral load at baseline, an association that persisted over time. Additionally, the presence of semen in CVL at baseline was associated with detection of HIV in the
genital tract (OR 13.08, 95% CI 2.55, 7.72), suggesting that some of the virus detected may be from male partners. In this study, over half of the male partners were HIV-infected.
There were also several presentations examining the male genital tract that have potential implications for sexual trans-mission to women. A small, prospective study examined the prevalence of HIV drug resistance in semen in men on stable HAART regimens with concomitant acute sexually transmitted disease (STDs) [Taylor, Abstract 373-M]. Previous studies in antiretroviral naïve men have shown that STDs increase seminal HIV shedding, thus facilitating HIV transmission. What has not been previously addressed is whether a patient with good virologic control on HAART also experiences viral rebound in the genital tract with concurrent STD acquisition and the implications this might have for the shedding of resistant virus.
Six of 24 men with acute STDs had detectable virus in both the plasma and the semen at the time of infection with STDs; 4 of the 6 had detectable primary drug resistance mutations, with minimal discordance between resistance patterns in the blood and semen. Intercurrent STDs may have the ability to disrupt otherwise effective treatment, both locally in the genital tract and systemically in the plasma, and in doing so increase risk for development of drug resistance. This has implications for control of disease on an individual level, but may also have broader implications for sexual transmission of drug resistant variants.
The differential penetration of antiretroviral drugs among physiologic compartments, including the genital tract, is also important to maintain control of HIV in the individual and to prevent sexual transmission of HIV-infection. Previous studies have suggested that in general, penetration of protease inhibitors into the male genital tract is poor, while nucleoside analogs and NNRTIs penetrate well. A small study of 4 men found that lopinavir also appears to have poor penetration into semen [Sankatsing, Abstract 439-W]. Poor penetration of protease inhibitors into seminal fluid may increase the risk of sexual transmission and possible transmission of resistant strains.
Sex Differences in Viral Load and Progression
In an analysis of 9 cross-sectional and 4 longitudinal studies, viral load measurements were compared in HIV-infected men and women [Gandhi, Abstract 775-W]. After adjusting for confounders, women had consistently lower viral loads than men at similar stages of infection, which is consistent with earlier reports. Possible explanations include sex differences in immune modulation, immune function variability over the ovulatory cycle, and lower CCR5 density in women. In a retrospective cohort of 229 patients (35% women), the effect of sex on long-term durability of antiretroviral therapy and CD4 count rise was evaluated [Wilkin, Abstract 777-W]. In this analysis 7.5% of women failed to reach undetectable viral load compared
with 19.5% of men (p=.02). Women achieved an undetectable viral load more often, even after adjusting for baseline CD4 count, viral load and prior NRTI use. Women had a lower baseline viral load (p=.004) and a trend toward higher CD4 counts (p=.09). They were also less likely to have a history of an AIDS defining illness (p=.002). Once reaching undetectable viral load, virologic failure did not differ by sex, and CD4 count rise after starting antiretroviral therapy was similar. There is still no compelling reason that guidelines for antiretroviral therapy should be different for women and men, however.
The recent reports of 3 maternal deaths due to lactic acidosis in women who had been on long-term therapy including d4T and ddI led to questions about whether pregnancy might be a time of greater vulnerability to lactic acidosis. Although this question has not been answered, a study presented by Lonergan that examined the incidence of symptomatic hyperlactatemia in adults on NRTIs may add other pieces to the puzzle [Abstract 35]. The risk of this condition was found to increase more than two-fold for each additional NRTI used in a regimen; in dual NRTI-containing regimens, combinations of d4T/ABC and d4T/ddI conferred the greatest risk. With triple NRTI combinations, d4T/ABC/3TC and d4T/ddI/3TC confer greatest risk. These
findings may provide some rationale for closer monitoring of symptoms and a low clinical threshold for checking lactate levels in pregnant women on NRTI regimens.
Cardiovascular disease risk is of increasing concern as a potential long-term toxicity associated with effective anti-retroviral therapy. Although heart disease rates are generally lower in women than in men until after menopause, U.S. women with HIV-infection may be more likely to have risk factors for cardiovascular disease than U.S. women in general. A cross-sectional study in 74 HIV-infected women measured concentrations of cell adhesion molecules (CAM), inflammatory markers that have been associated with atherosclerotic risk [Bausserman, Abstract 693-T]. Compared with historical controls, CAM concentrations were elevated in HIV-infected women and were related to lipoprotein concentrations, but they did not appear to be
related to treatment regimen or to time on treatment. These findings may reflect an additional risk of vascular disease in HIV-infected women.
Osteopenia, osteoporosis, and osteo-necrosis have also been associated with HIV-infection and its treatment. Arnsten described a cohort of 40 peri- and post-menopausal women (19 HIV-infected and 21 HIV-negative) who underwent bone density scan (DEXA) of the lumbar spine, hip, and total body [Abstract 717-T]. All HIV-infected women had taken anti-retroviral therapy, and 55% had been on a regimen that included a protease inhibitor (mean duration 48 months). After adjustment for age, no association was found between HIV-infection or PI exposure and reduced bone mineral density (BMD), although the sample size was small. In a 72-week cohort study reported by Mondy, changes in BMD were evaluated in 108 HIV-infected men and 17
HIV-infected women, along with serum and urine markers of bone turnover [Abstract 718-T]. Despite a mean age of 41 years, the prevalence of bone loss was high (46%). Factors associated with decreased BMD included known risk factors for bone loss, such as steroid use, smoking, low BMI, and a history of significant weight loss or wasting. Use of protease inhibitors was not significantly associated with decreases in BMD after controlling for other risk factors.
Both of these studies suggest that well-recognized risk factors for osteopenia and osteoporosis are associated with loss of BMD density in HIV-infected individuals and that HIV-infected women are at increased risk for these conditions after menopause. Risk factors for bone loss, including menopause, should be routinely assessed in HIV-infected women, and there should be a low threshold for bone density screening.
Two presentations addressed what are perhaps the most common gynecologic manifestations of HIV disease, human papillomavirus (HPV) infection and cervical dysplasia. A randomized multi-arm clinical trial compared observation versus cryotherapy in women with biopsy-confirmed low grade squamous intra-epithelial lesion (LSIL) and cryotherapy versus loop electrosurgical excision procedure (LEEP) in women with high grade squamous intra-epithelial lesion (HSIL) [Wright, Abstract LB16]. Women who had unsatisfactory colposcopy had either cervical conization or LEEP. One hundred and twenty-two HIV-infected and 257 HIV negative women were included. Mean follow-up was 10 months for HIV-infected women and 11 months for women without
HIV. All treatment modalities were less effective in women with HIV-infection than in women without HIV, and no single treatment type appeared to be superior. Although HIV-infected women with LSIL had significantly lower spontaneous regression rates (24%) than HIV negative women (61%), the rates of progression to biopsy-confirmed HSIL were low in both groups (4% vs 9%, respectively, p=NS). Only 56% of HIV-infected women with LSIL who were treated with cryotherapy had normal findings at follow-up, compared to 95% of HIV negative women with LSIL and cryotherapy. These findings are not surprising in light of previously published studies, but do suggest that conservative observation of confirmed LSIL is the most reasonable course of
action.
Ellerbrock and colleagues examined serial vaginal HPV-DNA levels in 40 HIV-infected women with at least 3 months of follow-up [Abstract 119]. There were no significant differences between women on successful HAART (consistently undetect-able plasma viral load) compared with those not on HAART in the proportion with increased, decreased, or unchanged HPV DNA levels. In multivariate analysis, HAART had no effect on HPV DNA level after controlling for CD4 count and plasma viral load. Although limited by small numbers and short follow-up, this study contributes to a growing body of literature suggesting that effective antiretroviral therapy is not going to have a dramatic impact on HPV infection or progression of cervical dysplasia, and close monitoring will be required.
In the end, the studies discussed above offer the following “take-home” messages:
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