Important note: Information in this article was accurate in November 2002. The state of the art may have changed since the publication date.
Attention to HIV's devastating effect on the lives of women around the globe continues to grow, and women's issues were well represented at the XIV International AIDS Conference.This article presents highlights from the conference (complete coverage can be found on the Johns Hopkins AIDS Service website, http://hopkins-aids.edu).
Developed Countries: Observational data on the use of HAART in pregnancy from the U.S. [Morris, Abstract WePeB5917], Italy [Melzi, Abstract MoPeD3682], Brazil [Nogueira, Abstract WePeB5912], and Argentina [Coll, Abstract WePeC6269] continue to show the lowest rates of MTCT with these regimens. Out of a total of 414 women on HAART in these uncontrolled series (data on mode of delivery and viral load was not consistently reported), there was a transmission rate of 0.5%.
This would seem to be a good omen for the ultimate eradication of perinatal HIV/AIDS in areas where HAART is available and accessible. However, a report from the Pediatric Spectrum of HIV Disease cohort in the U.S. demonstrated that many opportunities for perinatal HIV prevention are still missed [Peters VB, et al. Abstract ThOrD1429]. In an examination of HIV-exposed infants between 1996 and 2001, a missed opportunity for prevention of MTCT was identified in 56% of cases. Of these, 18% of mothers had no prenatal care, 29% had prenatal care but were not tested for HIV infection, and 9% were known or found to be HIV-infected but did not receive antiretroviral prophylaxis. Illicit drug use was a significant predictor of lack of prenatal care. These findings support current recommendations by the American Medical Association, the Institute of Medicine, the CDC, and the American College of Obstetricians and Gynecologists that HIV testing be made a routine part of antenatal care for all women.
Developing Countries: Prevention of MTCT continues to garner major attention as the gulf between the developing world, where over 95% of new infant infections occur, and the developed world, where availability of HAART has led to near eradication of pediatric AIDS, continues to widen. In low-resource settings where HAART is not yet available, clinical trials have demonstrated that short courses of AZT, AZT/3TC, or nevirapine (NVP) are all associated with reductions in MTCT in both breastfeeding and non-breastfeeding populations. These may have relevance for settings in developed countries when HIV infected women present late in pregnancy or in labor without having had prior treatment.
The success of NVP in reducing MTCT has prompted further study of regimens combining AZT and NVP given to the mother and/or newborn to determine whether these regimens might reduce MTCT further. In a late breaker session, Lallemant and colleagues reported preliminary results of a randomized, double-blind, placebo-controlled clinical trial in Thailand comparing (1) AZT beginning at 28 weeks and continuing through labor plus 1 week of AZT given to the newborn (reference regimen), (2) the reference regimen plus NVP given to the mother in labor and to the newborn, and (3) the reference regimen plus intrapartum NVP only [Abstract LB22]. At the first interim analysis the reference arm of AZT alone was discontinued because it was associated with a significantly higher transmission rate than the NVP intrapartum/neonatal arm (p<0.001). Enrollment continues in the two NVP arms. It should be emphasized that in the setting of a developed country, where most women receive HAART and where elective C-section is commonly employed, the addition of the intrapartum/newborn NVP regimen to existing HAART regimens did not offer additional benefit [Cunningham CK, et al. J Infect Dis 2002 Jul 15;186(2):181-8].
Two studies examined the use of AZT and NVP for post-exposure prophylaxis with newborn-only administration. This is an important topic to explore, since in many areas of the world, and especially in low resource settings, women of unknown HIV status may present in labor and may deliver before HIV status can be determined or before antiretroviral prophylaxis can be administered to the mother. Furthermore, the effectiveness of post exposure prophylaxis given to the newborn alone would eliminate the risk of precipitating antiretroviral resistance in mothers (although similar concerns would remain about resistance in the infant). In an open label, randomized clinical trial in Malawi, a single dose of NVP plus one week of AZT provided significantly more protection than a single dose of NVP alone [Taha TE, et al. Abstract ThOrD1427]. However, in a trial from South Africa, HIV-exposed infants randomized to NVP vs 6 weeks of AZT had statistically similar transmission rates at 6 weeks [Gray, Abstract LB13].
The feasibility of NVP monotherapy for prevention of MTCT has been tempered by concerns about resistance, since NNRTI resistance was detected in 19% of women in HIVNET 012 at 6 weeks postpartum. In a late breaker poster session, Sullivan and colleagues reported on selection of resistance mutations in women and infants enrolled in the SAINT trial, in which pregnant women were randomized to receive two doses of NVP plus single dose NVP to the infant at 72 hours after birth, vs AZT/3TC in labor and for one week after delivery for mother and infant [Abstract LB9024]. NVP resistance mutations were detected at 6 weeks post-partum in 74 of 111 (67%) women who received NVP, but no AZT/3TC resistance was detected in the 37 women receiving this therapy. At 9 to 12 months, 78% of 36 evaluable women with initial NVP resistance had reversion to wild-type virus. Of 40 infected infants exposed to NVP, 53% had NVP resistance mutations at 4 to 6 weeks of life.
More reassuring was a report from Thailand which found NVP resistance in only 5% of mothers at 1 month post-partum when single-dose NVP was combined with short course AZT from 34 to 36 weeks to labor, intrapartum, and 4 weeks to the infant, [Leelawiwat W, et al. Abstract MoPeB3124]. Three infants were infected and one had NVP resistance mutations. No AZT resistance was detected in mothers or infected infants. These data suggest that the risk of developing resistance with preventive therapy for MTCT may be reduced by using combination nucleoside therapy or adding a nucleoside to NVP, compared with NVP monotherapy. These studies confirm the need for further efforts to minimize both MTCT and the development of antiretroviral resistance in resource-poor settings.
Both health care providers and pregnant women frequently raise concerns about drug-related birth defects associated with the use of antiretroviral therapy. A report from the Antiretroviral Pregnancy Registry should be reassuring. A review of birth defects in infants exposed to antiretroviral agents in the first trimester through January 2002 found a rate of 24 per 952 live births, which is not an increase over the general population-based prevalence. Rates were similar with exposure to regimens with and without protease inhibitors [Garcia PM, et al. Abstract WePeB5955]. These data and others [Tuomala RE, et al. N Engl J Med 2002 Jun 13;346(24):1863-70] suggest that the risk of birth defects and adverse pregnancy outcomes using currently available antiretroviral agents is minimal, the notable exception being efavirenz. However, ongoing surveillance is paramount, as the aggregate experience with antiretroviral therapy is still limited.
In a meta-analysis of 9 clinical trials evaluating the role of late post-natal transmission of HIV via breastfeeding (defined as infant infection diagnosed after 4 weeks of age with prior negative test[s]), 1509 children were evaluated, with a mean duration of follow-up of 12.2 months and mean duration of breastfeeding 6.8 months [Read JS, et al. Abstract TuOrB1177]. Overall transmission rate was 25% (378/1509). Of the infected children, timing of infection could be categorized in 179, and 36% of these infections were due to breastfeeding, reinforcing the significance of this mode of transmission between mother and infant.
In a prospective multi-center study from France involving women with hepatitis C infection, co-infection with HIV was a significant predictor of hepatitis C transmission to the infant [Barjoan, et al. Abstract WeOrC1379]. In 144 mother-infant pairs, the HCV transmission rate was 1% (1/107) in HIV-negative women, but 16% (6/37) in HIV-infected women (P<0.001). No infants were HIV-infected. Four of the six HCV-infected children born to HIV infected women were delivered by elective C-section prior to rupture of membranes, suggesting that vertical transmission of hepatitis C occurs prior to the time of delivery and that C-section is not protective. Women co-infected with HIV and HCV who become pregnant or are contemplating pregnancy should receive counseling about this issue and its potential implications.
There has been much interest in the effect of HAART on progression, recurrence and regression of human papilloma virus (HPV)-related disease; several studies presented in Barcelona fueled existing controversies. A prospective study of 154 HIV-infected women on different ART regimens and with negative PAP smears but high-risk HPV (HR-HPV) present at baseline, found that immune reconstitution with antiretroviral treatment was not associated with a decrease in HR-HPV persistence or a decreased incidence of cytologic/histologic dysplasia over a mean of 2.8 years [Lillo F, et. al. Abstract WePeB6047]. Similarly, 40 women with positive vaginal HPV were followed for at least 3 months after starting HAART and had no change in vaginal HPV viral load between two consecutive visits before and after starting HAART, even among those with successful virologic suppression [Conley LJ, et al. Abstract 7309].
In contrast, the Canadian Women's HIV study followed 132 women who had cervical dysplasia (18% of the cohort) [Hankins C, et al. Abstract WePeB5969]. Data were available for 99 women, and 10.5% were on HAART. Overall, progression of cervical lesions was seen at a rate of 3.4/100 patient years, with persistence in 34.7/100 patient years; none of the women on HAART had progression or persistence of cervical lesions at follow-up. Women with regression of cervical lesions were also more likely to be on HAART. In a retrospective cohort of 56 women who underwent excisional treatment for high-grade cervical dysplasia, predictors of recurrence included higher mean viral load (p=0.01), detectable viral load >400 c/mL (p=0.002), lower mean CD4 count (p=0.035), positive margins (p=0.05), and no antiretroviral therapy (p=0.019) [Keller J, et al. Abstract 2096]. Those women who were taking antiretroviral therapy at the time of follow-up were significantly less likely to have recurrence of cervical disease after excisional treatment (p=0.02). In summary, data about the effect of HAART on HPV and cervical dysplasia remain mixed, and guidelines for screening and management of cervical disease are unchanged in women on HAART.
Questions also remain about the predictive value of pap smear in HIV-infected women. Anderson and colleagues evaluated a subgroup from the HERS cohort, including 189 HIV-infected women (1200 patient visits) and 95 HIV-uninfected but high risk women (602 visits) with pap smear, HPV-DNA testing, colposcopy, and biopsy if indicated, at planned 6 month intervals [Abstract ThPeB7399]. HIV-infected women were significantly more likely to have abnormal biopsy results with normal pap smears, as compared with HIV-uninfected women. Risk factors for abnormal biopsy with normal pap included presence of HPV and CD4 <500 cells/mm3. However, 17 of the 19 HIV infected women with normal pap and dysplasia on biopsy were found to have an abnormal pap within one year of the discordant results. These data do not support the need for routine colposcopy in women with HIV but underscore the need for regular cytologic screening.
In summary, data continues to accumulate which suggest that the use of HAART and achievement of optimal viral load suppression is associated with the greatest reduction of MTCT, although there is increasing concern about resistance with single dose NVP for both mother and child. The identification of HIV infection in pregnant women is the biggest hurdle in reducing MTCT, which underscores the importance of current recommendations that routine testing be made a part of antenatal care for all women. Lastly, the effect of HAART on the natural history of cervical dysplasia remains unclear and recommendations for evaluation and careful follow-up are unchanged.
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