1st International AIDS Society (IAS) Conference on HIV Pathogenesis and Treatment
July 7-11, 2001
Buenos Aires, Argentina
Mechanisms and Timing of Mother-to-Child Transmission
John Sullivan, MD, from the University of Massachusetts gave an excellent overview of the current state of knowledge concerning mother-to-child HIV transmission (MTCT), which can occur in utero, during birth and delivery (intrapartum), or postpartum as a consequence of breastfeeding. The profile of in utero vs intrapartum infection is represented in Table 4.
Table 4. First Detection of HIV in Infants: Characteristics of In Utero vs Intrapartum Transmission
|Timing of Infection- Cord Blood||-First 48 Hours||-1 Week||-4-8 Weeks|
Intrapartum transmission occurs by the transmission of maternal HIV present in the vaginal secretions or blood via the fetal conjunctiva, gastrointestinal tract, or a break in fetal skin. In non-breastfeeding populations, approximately 65% of transmission is thought to occur in the intrapartum period. With regard to the precise timing of in utero HIV transmission, most recent evidence would suggest that the most vulnerable time is at the end of the second trimester and the beginning of the third trimester.
Breastfeeding is clearly a risk factor for MTCT and remains a major obstacle in reducing vertical transmission in resource-poor regions, where breastfeeding is very much the norm, and alternatives such as formula-feeding are expensive and serve to mark the woman as "different" and possibly HIV-infected. Approximately 75% of transmission due to HIV-infected breast milk occurs within the first 6 months. Risk factors for transmission through breast milk include younger maternal age, seroconversion during breastfeeding, prolonged duration of breastfeeding, and presence of mastitis or breast abscesses. Formula-fed infants have a 44% reduction in rates of HIV infection.
Eradication of MTCT in Resource-Rich Regions
Importance of maternal viral load and use of antiretroviral therapy. The seminal Pediatric AIDS Clinical Trials Group (PACTG) study 076 was exceedingly important, demonstrating a decrease in the transmission rate from 25.5% in the placebo group to 8.3% in those who received zidovudine. This regimen required a rather intensive zidovudine exposure, beginning at week 14 in the mothers, who received 300 mg twice daily or 100 mg 5 times per day. An intravenous loading dose of zidovudine was given at the onset of labor, with a continuous infusion of the drug (2 mg/kg) throughout the entire time of labor and delivery, followed by oral zidovudine (2 mg/kg per dose every 6 hours) to the infant for the first 6 weeks of life. The study was also important in that it provided the data to prove that maternal viralload was the most critical factor in predicting MTCT. However, as shown by Sperling and colleagues, even among women with the lowest viral loads, those who received zidovudine were statistically less likely to transmit HIV to their infants than were those who received placebo, as shown in Table 5.
Table 5. Effects of Maternal Viral Load and Receipt of Zidovudine in PACTG 076
|Viral Load- Transmission Rate:||--Among Zidovudine Recipients||--Among Placebo Recipients|
|< 1730 copies/mL||2.5%||7.1%|
|> 15,700 copies/mL||13.3%||41.7%|
The importance of antiretroviral therapy, even in women with very low viral loads, was also demonstrated by Ioannidis and colleagues, reporting from a collaborative study of 1202 women with plasma HIV-1 RNA levels less than 1000 copies/mL who were enrolled in 7 European and US prospective studies. MTCT occurred in a total of 44 women (3.6%), with statistically less likelihood of transmission if antiretroviral therapy had been given during pregnancy and/or delivery. Thus, of the 834 women who received antiretroviral therapy, the transmission rate was 1% (8 women), while transmission occurred in 36 (9.8%) of 368 women who did not receive antiretroviral therapy, even though their viral loads were less than 1000 copies/mL. This difference was highly significant (P < .001).
Subsequent to the initial PACTG 076 report, abbreviated regimens of zidovudine were also evaluated, and have been proven efficacious in preventing MTCT. In a study conducted in New York State, Wade and coworkers found that the trans mission rate among mothers who did not take zidovudine was 26.6%. However, in mothers who began zidovudine for the first time during delivery, the transmission rate was 10%, and in infants who first received zidovudine during the first 48 hours of life, without prior maternal exposure, the infection rate was 9.3% -- both of which were statistically less than the transmission rate among mother-child pairs who remained untreated. Other abbreviated regimens of zidovudine have also been studied, with proven efficacy.
The use of nevirapine in preventing MTCT has led to a practically feasible and affordable (US$5) method that might be applicable to resource-poor regions. Nevirapine has a long half-life (25-30 hours) and is lipophilic, and therefore is present in breast milk. An oral suspension is available, making administration to the newborn possible. The drug is potent, resulting in a 1.3 log10 copies/mL decrease in viral load 7 days after a single dose. PACTG study 316 evaluated the addition of placebo or nevirapine (200 mg administered to the mother during labor and 2 mg/kg to the infant at birth) to the antiretroviral regimen of pregnant women who were nevirapine-naive. After 1503 mother-child pairs had been enrolled, the study was stopped prematurely because the overall rate of MTCT was only 1% to 2%, making it impossible to show any incremental effect of nevirapine. Of importance, however, 104 women enrolled in PACTG 316 had plasma HIV-1 RNA levels > 400 copies/mL and were studied for the development of nevirapine resistance. A total of 5 (11%) of 46 women developed nevirapine resistance mutations after the single dose. These women have been followed for over 1 year, by which time the mutations can no longer be detected. Certainly, the development of resistance after single-dose exposure to nevirapine is of concern, although the long-term clinical consequences of these resistance mutations are not yet understood.
Mary Louise Newell, MD, discussed the recent finding of premature delivery (50% delivered by week 37) in HIV-infected pregnant women who had been given PI-containing antiretroviral regimens. The use of PIs may thus have a wider effect on the mother and infant than previously understood, mandating thorough additional study of HAART-treated pregnant women in the years ahead.
Using a human in vitro placental perfusion model, Peytavin and colleagues from France studied the perfusion of nelfinavir, noting that only 5.0% +/- 2.4% of the parent drug actually reached the fetal side of the circulation, with no evidence of placental metabolism of the drug. While not a major study in itself, the model is an interesting one that should prove useful in future studies of antiretroviral drugs used in an attempt to prevent MTCT.
Mode of delivery. The European Collaborative Study, based on 721 children born to 701 mothers, demonstrated that elective cesarean section (C-section) was associated with a decreased risk of MTCT (relative risk [RR] = 0.56), although these results were not statistically significant. A subsequent meta-analysis of North American and European studies, each one of which included at least 100 mother-child pairs, analyzed data from a total of 8533 mother-child pairs. After adjusting for the use of antiretroviral therapy, maternal stage of HIV infection, and infant birth weight, the risk of perinatal transmission was decreased by approximately 50% in those women who underwent elective C-section (OR, 0.43; 95% confidence interval [CI], 0.33-0.56). Similar results were found when the control population was limited only to those women with rupture of the membranes immediately prior to delivery. As presented by Newell, use of antiretroviral therapy during pregnancy and delivery, use of elective C-section, and avoidance of breastfeeding have all resulted in a decrease in the rate of MTCT in Europe to approximately 2%. According to Dr. Newell, up to 85% of HIV-infected pregnant women now undergo elective C-section in Europe, which is considerably different from the experience in the United States. It is important to mention, however, that elective C-section has been associated with complications in HIV-infected women, as published by Watts and colleagues and summarized in Table 6.
Table 6. Rate of Complications of Elective C-Section in HIV-Infected Women
|Complication||Planned C-Section (n = 37)||
Other C-Section (n =95)
|Vaginal Delivery (n= 365)|
|Amnionitis or endometritis||16%||27%||7%|
|Wound infection||5%||8%||< 1%|
In a multivariate analysis, factors associated with amnionitis or endometritis were C-section and African American race. In the question-and-answer period, when these issues were raised, Dr. Newell commented that the severity of these problems was relatively mild, thus not serving to negate the value of the procedure in preventing MTCT. Nonetheless, when Dr. Sullivan was asked if he would consider elective C-section in women who had undetectable viral loads, he replied that he would not, although he clearly stated that the issue of elective C-section remains an area of controversy, especially in women with low viral loads.
In concluding this discussion, Dr. Sullivan was asked for his recommendation regarding optimal antiretroviral therapy for HIV-infected pregnant women in resource-rich areas of the world. He replied that he would use zidovudine, lamivudine, and nevirapine, and would probably start therapy during the second trimester, since a substantial proportion of in utero transmission occurs at the end of the second trimester. With regard to this 3-drug antiretroviral combination, Coll and colleagues from Buenos Aires studied its safety and efficacy in a group of 36 HIV-infected pregnant women, accrued between May 1998 and February 2001. Their median age was 28 years, and 23 women were antiretroviral-naive. The median duration of pregnancy when therapy was initiated was 20 weeks (range, 12-36 weeks), and the median gestational age at delivery was 38 weeks (range, 24-40 weeks). After the 36 children had been monitored for a median of 24 weeks, all 29 babies who underwent 2 polymerase chain reaction tests during this period were uninfected. No mother discontinued therapy during pregnancy, and the median baseline viral load of 35,446 copies/mL fell to a median of 67 copies/mL by delivery. The only adverse event in the 36 infants was anemia, occurring in 5 (13.8%) and resolving spontaneously over time. This study, although small, confirms the short-term safety of this approach and its efficacy in preve nting MTCT. Thanks to Alexandra Levine, MD, and Medscape for article.