Despite increasing attention to women with HIV and pregnancy, and growing evidence of the effectiveness of various prophylactic and therapeutic ART regimens in reducing mother-to-child transmission (MTCT) in real-world and low resource settings, there was little new to report at the 3rd IAS Conference. However, there were some important updates from ongoing studies and a few important reminders of some fundamental principles of practice relating to women.

Nevirapine Resistance

There continues to be controversy about the development of nevirapine (NVP) resistance when this drug is used for prevention of MTCT–how often resistance occurs, what it means, and how to prevent it. Recent reports suggest that up to one-half of resistance that develops is not detected by conventional sequence analysis and that resistance can occur even when NVP is used with other ARV agents to prevent HIV transmission. Thus, this topic is a relevant concern, not only in the developing world, where the use of single-dose NVP (sd-NVP) is often the only option for reducing risk of MTCT, but also in resource-rich countries, where NVP may be used in combination with other agents prophylactically during pregnancy and stopped after delivery. Arrive and coworkers performed a meta-analysis of 8 existing studies addressing this issue involving a total of 887 women [Abstract TuPe5.2P15]. Using conventional testing 4-8 weeks after delivery, administration of maternal postpartum antiretrovirals was significantly associated with lower rates of resistance compared to sd-NVP alone (odds ratio 0.08-0.11) in a multivariate analysis. The use of other antepartum/intrapartum agents was not related to risk of resistance after adjustment. This analysis has some potential flaws: conventional resistance testing and aggregate data (some preliminary) were used, there was no information on information on viral subtype, and there was a potpourri of study designs. Nevertheless, the conclusion was supported by an update from the Treatment Options Preservation Study (TOPS) in South Africa, reported by James McIntyre [IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: (Abstract TuFo0204)]. This study examines one strategy for preventing the emergence of NVP resistance by giving zidovudine/lamivudine (AZT/3TC) intrapartum and for an additional 4 or 7 days postpartum after sd-NVP. With similar baseline median CD4 counts and viral loads, NVP resistance was detected at 6 weeks in 41/68 (60%) in the NVP-only arm vs 8/67 (12%) in the NVP/AZT/3TC (4 day) group and 7/68 (10%) in the NVP/ AZT/3TC (7 day) group. Furthermore, NVP resistance in infected infants decreased from 6/9 (66.7%) with NVP alone compared to 0 in the NVP/AZT/3TC arms. Viral load has been shown to be an independent variable associated with development of resistance, and in both AZT/3TC arms, the nadir viral load was <500 c/mL compared to 8,300 c/mL in the NVP only arm.

The fact that resistance fades in the absence of drug pressure after a single dose of NVP has been metabolized has led a number of people to question the significance of NVP resistance in this setting. Lallemant presented an update from a study attempting to address this question in terms of maternal response to NNRTI-based ART after exposure to sd- NVP for the prevention of MTCT [Abstract TuFo0205]. After 18 months of follow-up of 191 women exposed to sd-NVP and 44 nonexposed women, there remained a significant difference in those achieving a viral load <50 c/mL (42% of exposed vs 58% non-exposed, P=0.05), suggesting that exposure to NVP and development of resistance does make a difference in response to subsequent therapy that contains NVP. On the other hand, in those women with a viral load <50 c/mL at 6 months, there was no significant difference in either immunologic or virologic response at 18 months, suggesting that the disparity in response does not increase over time.

This subject is far from settled, and other randomized trials and observational studies are ongoing or planned that will further explore the significance of NVP resistance in the setting of the prevention of MTCT, as well as strategies to prevent it.

Other Antiretroviral Agents

Concerns have been raised about the use of atazanavir (ATV) in pregnancy, because of the associated indirect hyperbilirubinemia and uncertainty about whether this may increase risk of kernicterus in the newborn. Morris reported on ATV exposure during pregnancy in 9 women; mothers had good immunologic and virologic response and tolerated therapy well, with total bilirubin at term ranging 0.3-3.5 [IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd:(Abstract TuPe5.2P01)]. Rates of neonatal hyperbilirubinemia were within the range of reported rates in the general population.

Enfurvitide (T-20, ENF) is being increasingly used as part of salvage regimens. Brennan-Benson described two pregnancies with ENF exposure; in both the drug was well-tolerated and no placental transfer was demonstrated [IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: (Abstract TuPe5.2P06)]. In pregnant patients who are on salvage therapy with ENF and unable to achieve an undetectable viral load, elective Cesarean delivery should be considered to optimize prevention of perinatal transmission.

An unusual study of the pharmacokinetics of EFV in women who were generally inadvertently treated during pregnancy found that trough levels of the drug were similar during pregnancy to those in nonpregnant adults, with no differences between trimesters of pregnancy [Cassard B, et al. IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd:( (Abstract WePe3.2C12)]. Efavirenz is now a FDA category D drug, with documented teratogenicity in pregnancy. However, use after the first trimester, when the risk of birth defects has passed, may be considered when there are no good alternatives.

And Don’t Forget...

Despite the enormous strides in prevention of MTCT of HIV, there are still missed opportunities for preventive interventions, which can have devastating effects on the mother, her child and the entire family. D’Ippolito and colleagues reported an impressive 1.2% perinatal transmission rate among 646 infants in Latin America and the Caribbean as part of the NICHD International Site Development Initiative [IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd (Abstract TuPe5.1P03)]. Five of the eight infected infants illustrated situations where transmission may have been prevented, including failure to adequately suppress viral load, use of AZT alone in the presence of high viral load, late start of antiretroviral therapy, and vaginal delivery despite high viral load in late pregnancy.

Finally, studies from Brazil [Friedman R, et al. IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: (Abstract TuPe5.5P26)] and Italy [Compostella S, et al. IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: (Abstract TuPe5.5P14)] reported surveys of HIV-infected women’s desire to become pregnant. Of 173 Brazilian women, 18.5% expressed a desire to conceive within the previous 6 months; of 122 Italian women with a mean age of 40, 77% expressed some desire to become pregnant. Although this desire was significantly attenuated with consideration of their HIV status, with primary concerns about health of a child, the availability of HAART appeared to encourage consideration of pregnancy. These studies and others confirm the need to include assessment of pregnancy plans and preconception counseling as part of the primary care for HIV infected women of childbearing age.

Summary

There continues to be controversy about the development of NVP resistance when this drug is used for prevention of mother-to-child transmission. Despite presentations on the subject at this and other meetings, the subject is far from settled, and randomized trials and observational studies are ongoing or planned that will further explore this critical issue.

Despite concerns about indirect hyperbilirubinemia with ATV, one study showed that rates of neonatal hyperbilirubinemia were within the range of reported rates in the general population. A report of two pregnant patients on ENF indicate good tolerability and no transmission; however, elective C-section may be recommended in patients on ENF who do not achieve an undetectable viral load. A study of pregnant women inadvertently given EFV suggests trough levels similar to women who were not pregnant.

Finally, additional studies remind providers of the need to be vigilant regarding missed opportunities to prevent HIV transmission and to include discussions of pregnancy plans as part of primary care.

20050901
JH2005-09-03

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