Special Delivery: HIV and Pregnancy
The significant reduction in the rate of transmission of HIV from mother to child (vertical transmission) is one of the true success stories in AIDS research today. In many industrialized nations, rates of transmission have dropped substantially to below 5%. Success has been more difficult to attain in the developing world, where traditional obstacles to care and treatment impede the implementation of sometimes costly and complex interventions aimed at preventing vertical transmission.
While the number of HIV-infected infants born in the US has decreased to an average of 200 to 300 per year, the number of babies infected worldwide through vertical transmission and breast-feeding is projected to reach 700,000 in 1999. However, recent studies indicate that simpler, less expensive interventions more appropriate to resource-poor countries are also effective. In addition, efforts to address other risk factors associated with vertical transmission have revealed more information on the roles of breast-feeding, maternal viral load and elective cesarean sections.
Preventing Transmission Using AZTThe landmark clinical trial ACTG 076 demonstrated that a three-part course of AZT treatment (administered before birth orally, during labor with an IV infusion, and to the newborn orally) reduced the rate of vertical transmission by two thirds, from 25% to 8%. While this regimen has become the standard of care in industrialized countries, it is not economically feasible for use in the developing world. Researchers have been evaluating abbreviated courses of treatment overseas that may be more affordable and practical.
A recent trial performed in a non-breast-feeding population in Thailand studied the use of AZT beginning in the last month of pregnancy: at week 36, as opposed to week 14 in the 076 regimen. During delivery the drug was administered orally, not intravenously, every three hours. No drug was delivered to the newborn. This simplified short course regimen resulted in an impressive 51% reduction in the rate of vertical transmission from 18.9% to 9.4%.
It may be possible to delay AZT treatment even longer and still achieve significant improvements in the rate of vertical transmission. A chart review of 939 HIV-exposed infants conducted by the New York State Department of Health demonstrated that even when treatment did not begin until labor, transmission of HIV was often prevented. The rate of vertical transmission was also significantly reduced when AZT was administered only to the infants, beginning within 48 hours postpartum.
When treatment was begun during pregnancy, the rate of vertical transmission was 6.1%, when begun during labor and delivery, the rate was 10% and when begun within the first 48 hours of life, the rate was 9.3%. In the absence of AZT treatment, the rate of vertical transmission was 26.6%. In the U.S., the standard of care remains the full three-part 076 protocol, which has the greatest potential to reduce vertical transmission. However, the results of this study indicate that it is still worthwhile to initiate AZT therapy during labor and delivery, or immediately after birth, regardless of perinatal treatment.
Judging NevirapineThe short course Thai regimen costs about $70 per intervention (with a price reduction from the drug manufacturer), significantly less than the full 076 regimen, which costs $800. However, many developing countries spend an average of only about $5 per person annually for healthcare, effectively putting even the short course treatment out of range of the vast majority of women in resource-poor areas. In response to this, HIVNET 012 was undertaken. This study showed the benefits of only two doses of nevirapine (viramune) -- one to the mother and one to the infant -- in decreasing the rate of vertical transmission.
Nevirapine has several important advantages over AZT. It is a rapidly acting drug because, unlike AZT, it does not need to be metabolized before becoming active. Nevirapine crosses the placenta very quickly and reaches therapeutic levels in the fetus within 30 minutes of administration to the mother. Nevirapine also has an extremely long half-life (the time required for half the quantity of a drug to be metabolized) of 46 hours in the newborns and 61 hours in the mother. A possible drawback to the use of nevirapine is the potential for rapid development of HIV resistance to the drug.
Results of the HIVNET 012 study were reported in September at the Second Conference on Global Strategies for the Prevention of HIV Transmission from Mothers to Infants in Montreal. The trial, conducted in a breast-feeding study population in Uganda, compared the efficacy of short course AZT versus nevirapine in 626 HIV-positive pregnant women. The nevirapine regimen consisted of a single 200 mg oral dose at onset of labor and a single 2 mg/kg dose to the infant within 72 hours of birth. The AZT regimen included an oral loading dose of 600 mg administered at the onset of labor followed by 300 mg administered every three hours until delivery and one week of 4 mg/kg AZT twice daily for the infant.
The drug coverage period of the two regimens was equivalent because of the long half-life of nevirapine. A single dose given to the mother and infant maintained the nevirapine at therapeutic levels for at least seven days. This is similar to the one week of exposure in the infants receiving the AZT regimen, which has a much shorter half-life, requiring twice daily dosing for seven days (assuming that the mother is giving her baby the prescribed dose).
The HIV infection rates at three days of age were essentially equivalent in the two groups: 8.2% in the nevirapine arm and 10.4% in the AZT arm. However, at 6-8 weeks of age, the difference in the rate of transmission was statistically significant between the two treatment groups: 11.9% for nevirapine and 21.3% for AZT. The benefit persisted, and by 14-16 weeks the difference had increased, with a 13.1% rate of transmission in the nevirapine group and a 25.1% rate in the AZT group. The efficacy of nevirapine when compared to AZT was 47% greater. Both drug regimens were well tolerated.
The Role of Breast-FeedingIn industrialized countries, it is not recommended that HIV-positive women breast-feed their infants, as this is a known route of vertical transmission. However, breast-feeding continues in many parts of the developing world due to lack of affordable and safe infant formulas. Breast-feeding can provide protection against diarrhea, respiratory disease and malnutrition. Mothers who do not nurse their infants may be stigmatized in their communities.
However, breast-feeding limits the potential of short course antiretroviral regimens in minimizing rates of vertical transmission in the developing world. The Thai short course AZT regimen mentioned above achieved a 50% reduction in vertical transmission in a non-breast-feeding study population. When this same regimen was evaluated in the Ivory Coast and the mothers were permitted to breast-feed, the efficacy fell to 30% by the time the babies reached 450 days of age.
Recent studies report that breast-feeding increases the risk of HIV transmission from mothers to babies by as much as to 16%. In 1999, over 200,000 babies are projected to become infected with HIV through breast milk. In view of the obstacles to the elimination of breast-feeding among HIV-positive women in developing countries, approaches to preventing transmission were recommended at the Montreal conference. These included providing antiretroviral therapy during breast-feeding, preventing HIV seroconversion in HIV-negative mothers during breast-feeding, treating breast sores and other infections, such as mastitis, in the mother and mouth sores in the infant, Vitamin A supplementation in the mother and possibly avoiding mixed feeding (combining breast-feeding and formula feeding).
A study reported at the conference documented that alternatives to breast milk can be successful when provided to women in developing countries. The first head-to-head comparison of the effects of formula feeding versus breast-feeding was conducted in Kenya. All women had access to treated municipal water and received instructions on proper infant feeding techniques. Adherence was 96% with breast-feeding and 70% with formula feeding. At 24 months, the rate of HIV infection was 20.5% in the formula group and 36.7% in the breast-feeding group. Transmission via breast milk was highest in the first week of life and by six months of age, 75% of breast milk infections had already occurred. At 24 months of age, mortality rates were comparable between both arms (24% for breast-fed infants versus 20% for formula fed).
Viral Load, Transmission and HAARTAnother important factor in the risk of vertical transmission is maternal viral load. Many studies have reported that women with high viral loads transmitted the virus more often than women with low viral loads. The investigators of the clinical trial, ACTG 185, found that the risk of transmission was lowest in women with fewer than 500 copies of HIV . There were no cases of vertical transmission among women with undetectable viral loads. However, transmission occurred at all levels of detectable HIV.
This finding underscores the importance of treatment strategies aimed at reducing viral loads. Lynne Mofenson, MD, the study's principal author, stated, "In addition to improving a woman's overall health, reducing the level of HIV may also reduce a woman's chance of giving birth to a child with HIV infection." Dr. Mofenson cautions that although none of the women in this study transmitted virus to their children, there have been reports of transmission even from women who had undetectable viral levels.
Although opinions vary, there is a consensus that HIV-positive pregnant women should be treated with regimens that would not be considered substandard in non-pregnant women. However, AZT monotherapy is still the official recommendation for management of HIV-positive women whose health status is such that therapy would not normally be indicated. In actual practice, the use of antiretroviral therapy during pregnancy is changing. An analysis of data on 1,202 pregnant women in the WITS study indicated that, today, approximately one third of women in this study population still receive AZT monotherapy. AZT and a second antiretroviral, usually 3TC, are used by another third and the remaining 33% are being prescribed HAART regimens.
The average viral load in women in the WITS study who transmitted the virus to their babies was nearly three times higher than the average viral load of women who did not. In addition, the use of AZT therapy was significantly associated with a lower rate of vertical transmission, although treatment with AZT was not associated with decreased maternal viral load. Lead author Patricia Garcia, MD, notes, "This supports previous studies that found AZT therapy during pregnancy reduces the risk of perinatal transmission, but not solely as a result of reduction in maternal HIV levels. The same may not be true for combinations of potent antiretroviral drugs that are capable of reducing maternal viral load to undetectable levels."
Since HAART achieves the goal of reducing HIV viral load to undetectable levels and viral load is a significant factor in vertical transmission, it may be a good choice for HIV-positive pregnant women who have access to therapy. However, there is limited experience using these drugs during pregnancy, and their possible benefits must be weighed against the lack of information on potential long-term effects of children exposed to them.
Elective Cesarean SectionsSince a large proportion of vertical transmission occurs at or near delivery, intervention at this time might prove beneficial. Elective (non-emergency) cesarean section prior to the time the mother's water breaks can prevent the infant from being exposed to maternal blood and secretions. In an analysis of over 8,000 women, risk of vertical transmission was reduced by over 50% with elective cesarean section compared to other modes of delivery. In women who received antiretroviral therapy, the rate of transmission was 2% with elective cesarean section and 7.3% with other modes of delivery. In women who were not on antiretroviral therapy, the transmission rates were 10.4% with elective cesarean and 19% with other modes of delivery. Data for this analysis were obtained at a time when HAART was not available. Therefore, there is no information as to whether elective cesarean sections would provide any added benefit for women on HAART with undetectable viral loads.
As a prevention intervention, antiretroviral therapy is clearly a better option than elective cesarean section, as treatment during pregnancy may prevent transmission in the prenatal period and also provides post-exposure prophylaxis to the infant. An elective cesarean section may be beneficial in the following scenarios: women who have not taken antiretrovirals during pregnancy; women with persistent or rising viral loads; and women with difficulty adhering to HAART.
Current US Public Health Service Guidelines do not recommend universal cesarean sections in HIV-positive pregnant women. Instead, women should be apprised of all available information and individualized decisions should be made jointly between the physician and the patient.
Since cesarean section is major surgery, there are associated complications for the mother. While cesarean sections are generally quite safe in industrialized countries, some studies have found that HIV-positive women have an increased risk of post-operative complications. Furthermore, surgical procedures may not be an option for the majority of women in resource-poor countries with limited health care infrastructures and budgets.
ConclusionVertical transmission is considered by some to be a preventable occurrence. In order for all women to benefit from the advances that have been made in this field, major initiatives are needed to provide education, health care, treatment and empowerment to women. Effective interventions applicable in the developing world have been developed, but it remains to be seen if even these simplified regimens can be widely implemented. As Mark Wainberg, PhD, Co-Chair of the Conference on Global Strategies for the Prevention of HIV Transmission stated, "We now have the scientific ability to make a difference. Does the world have the will to translate scientific achievement into practical success?"
This article was provided by AIDS Community Research Initiative of America. It is a part of the publication CRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.