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Tale of Two Epidemics: The Continuing Challenge of Preventing Mother-to-Child Transmission of Human Immunodeficiency Virus
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The Journal of Infectious Diseases 2003;187:721-724
Lynne M. Mofenson
Pediatric, Adolescent, and Maternal AIDS Branch, Center for Research for Mothers and Children, National Institute of Child Health and Human Development, National Institutes of Health, Rockville, Maryland
The results of the South African Intrapartum Nevirapine Trial (SAINT), published in this issue of The Journal of Infectious Diseases, provide further evidence of the safety and efficacy of short-course antiretroviral prophylaxis regimens for the prevention of mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV). SAINT compared 2 intrapartum/postpartum antiretroviral regimens, multiple-dose zidovudine/lamivudine and single-dose nevirapine, that had been shown in previous, separate clinical trials to be effective in preventing MTCT and found that both regimens had similar efficacy and safety. SAINT is the fifth clinical trial in breast-feeding populations published since 1999 that has demonstrated the safety and efficacy of different short-course antiretroviral regimens for preventing MTCT. However, the results of these trials appear to have had little impact on the perinatal HIV epidemic in resource-limited countries, bringing into sharp focus the differences in the perinatal epidemic between resource-rich countries and those with limited resources.
It has been less than a decade since the Pediatric AIDS Clinical Trials Group (PACTG) protocol 076 demonstrated the efficacy of a 3-part antenatal, intrapartum, and 6-week infant zidovudine regimen in prevention of MTCT, initiating major changes in the perinatal HIV epidemic in resource-rich countries. Ten years ago, 6000 HIV-infected women gave birth each year in the United States, and 1600 of their infants became HIV-infected through MTCT annually. Within 1 year of the publication of the results from PACTG 076, widespread implementation of the zidovudine prophylactic regimen, coupled with recommendations for universal prenatal HIV counseling and voluntary testing, resulted in a decrease in transmission from 25% to 8% in this country. More recently, with the use of highly active antiretroviral therapy and elective cesarean delivery, transmission rates have decreased to <2%, and it is estimated that <400 infected infants are currently born each year in the United States. Similar reports of success have come from Europe.
What accounts for the dramatic and rapid success in reducing MTCT in resource-rich countries? The availability of a highly effective regimen that reduced perinatal transmission by nearly 70% without excess toxicity to the mother or the infant was clearly a key element. But without widespread incorporation of this regimen into clinical practice, no population-wide effect would have occurred. After the release of the results of PACTG 076, the US Department of Health and Human Services rapidly convened a Public Health Service task force to review the trial results; the task force published guidelines within 6 months for broad use of this regimen and soon thereafter for universal voluntary HIV counseling and testing for pregnant women. In addition, in the United States, the almost universal availability of clean water, government programs to subsidize the purchase of formula for women living in poverty, and cultural acceptability of formula feeding have allowed HIV-infected women to avoid breast-feeding, thereby preventing postnatal transmission of HIV.
Unfortunately, the complexity and cost of the PACTG 076 zidovudine regimen has restricted its applicability to resource-rich countries. The World Health Organization estimated that 3.2 million children were living with HIV infection at the end of 2002, the vast majority infected through MTCT. More than 90% of these perinatal infections occurred in resource-limited countries. The results of SAINT and of 6 other large, randomized, controlled clinical trials conducted in resource-limited countries since 1999 (4 of which involved breast-feeding populations) confirm that nearly 50% efficacy in reducing MTCT can be achieved with several short, simple, effective, and inexpensive antiretroviral prophylaxis regimens, including regimens of zidovudine alone, a combination of zidovudine and lamivudine, and single-dose nevirapine. Moreover, the SAINT data provide further evidence of the safety of the single-dose nevirapine and short-course zidovudine/lamivudine prophylaxis regimens; no serious drug-related adverse events were observed in the >1300 women and infants enrolled in the study.
Thus, the lack of an affordable, safe, and effective intervention can no longer be viewed as an insurmountable barrier to prevention of MTCT in resource-limited countries. However, in contrast to rapid and widespread implementation of programs to reduce MTCT in resource-rich countries, these effective short-course regimens have had slow uptake in resource-limited countries, and the momentum of the epidemic has continued unabated, with >800,000 infants newly infected during 2002 alone. Significant economic, social, and governmental barriers to implementation of MTCT prevention programs have existed in resource-limited countries. In addition, HIV transmission through breast-feeding remains a significant problem in countries where safe replacement feeding is not possible.
As pharmaceutical companies have initiated programs to provide drugs for prevention of MTCT at greatly reduced or no cost to resource-limited countries, the cost of MTCT programs has become tied less to financing the purchase of the antiretroviral prophylactic regimen than to developing and supporting the mother-child health care infrastructure required for implementation of such programs, which has remained problematic for many resource-limited countries. The simple intrapartum/postpartum zidovudine/lamivudine and nevirapine prevention regimens studied in SAINT can be implemented even in settings in which women may have only limited antenatal care or present to the health care system for the first time in labor. Women must, however, be able to access the health care system to be able to receive such interventions, which may be difficult in rural settings, in which many deliveries occur at home with traditional birth attendants. There is a need for the development of innovative delivery systems for provision of preventive regimens in such settings.
The availability and acceptance of voluntary and confidential HIV counseling and testing services are critical in enabling pregnant women to determine their HIV infection status and to be able to access preventive interventions, and additional resources will be required in many settings to introduce such programs. The Joint United Nations Programme on HIV/AIDS and nongovernmental organizations such as the Elizabeth Glaser Pediatric AIDS Foundation Call to Action program are providing funding for infrastructure development for MTCT prevention programs at sites in the developing world. Additional partnerships between donors; international, national, and local governments; and nongovernmental organizations will be essential to the development of effective and sustainable MTCT prevention and care programs.
However, inadequate funding and poor health care infrastructure are not the only obstacles. Even in settings where HIV counseling and testing services are available, the social stigma associated with HIV infection inhibits many women from using such services to learn their HIV infection status and, therefore, from taking steps to prevent transmission of HIV to their infants. The lack of availability of treatment for HIV infection or its complications in many resource-limited countries leads to an individual and societal perception that there is no benefit to be gained from knowledge of one's HIV infection status, which further increases the stigma associated with HIV infection.
There have been some successes in implementing prevention programs in resource-limited countries, with one of the key elements being support of the program by the health ministries and government. Thailand became the first resource-limited country to implement a national MTCT prevention program, which includes support of routine voluntary counseling and HIV testing for pregnant women and offers short-course zidovudine prophylaxis and infant formula to HIV-infected women. Other countries, such as Botswana and Cote d'Ivoire, are also in the process of implementing national MTCT prevention programs.
Prophylactic use of antiretroviral drugs for which a single genetic mutation can confer drug resistance, such as nevirapine or lamivudine, has been a concern. Nevirapine resistance has been detected at 6 weeks postpartum in 18% of women receiving single-dose, intrapartum drug, but resistant virus did not persist as detectable quasi species at 1218 months postpartum. The clinical significance of this finding is uncertain; theoretically, with reestablished predominance of wild-type virus, the efficacy of single-dose nevirapine prophylaxis for subsequent pregnancies is likely to be maintained. In addition, the response to therapy containing nonnucleoside reverse-transcriptase inhibitors in an individual for whom long-term therapy has previously failed, compared with an individual who has transient detection of resistance mutations after exposure to a single dose of nevirapine, may differ. Although further study is needed to evaluate response to future prophylaxis and treatment in women who have received single-dose nevirapine, the World Health Organization concluded that the established benefit of single-dose nevirapine in preventing MTCT outweighs the theoretical risks.
A remaining significant challenge in resource-limited countries is transmission of HIV through breast-feeding. Infected women in such settings have a significant dilemma: breast-feeding, although it provides substantial health and survival benefits to the infant and contraceptive, economic, and social benefits to the mother, is associated with risk of HIV transmission to the infant. Avoidance of all breast-feeding is the most reliable way to prevent postnatal transmission of HIV, and this is recommended in settings in which commercial infant formula is affordable and sustainable, clean water is widely available, hygiene and sanitation conditions are good, and deaths due to diarrhea and other infectious diseases are relatively uncommon because of adequate preventive and curative health care. This is not the case in much of the world.
SAINT, which included both formula-fed and breast-fed infants, has significantly contributed to our understanding of HIV transmission through breast milk. In SAINT, all infants received effective prophylaxis against intrapartum HIV transmission; in this context, breast-feeding was the most significant risk factor for MTCT. By age 8 weeks, breast-feeding accounted for an increase in the absolute risk of transmission of 6%; in multivariate analysis, there was a 2.2-fold increase in HIV infection among breast-fed versus formula-fed infants during the first 4 weeks of life and an additional 7.9-fold increase between ages 4 and 8 weeks.
Similar data from a randomized clinical trial of breast-feeding versus formula feeding in Nairobi, Kenya, indicated that approximately two-thirds of transmission through breast milk occurred during the first 68 weeks of life, with 75% occurring by age 6 months. In this issue of The Journal of Infections Diseases, the Kenya investigators report that, although viral shedding occurs throughout lactation, virus loads in colostrum and early milk are significantly higher than in mature breast milk, providing a possible explanation for the apparent higher risk of infant infection during the early breast-feeding period. Thus, although the risk of HIV transmission through breast milk persists for the duration of breast-feeding, the period of highest risk appears to be the first months of life. This is also the period during which breast-feeding provides the infant with maximum health benefits, in terms of infant nutrition and protection against diarrheal and respiratory infections. A number of ongoing and planned clinical trials will address whether short-course antiretroviral drugs given to the mother (including highly active antiretroviral therapy) and/or the infant during the lactation period, with early weaning by age 6 months, will reduce transmission through breast milk.
It is increasingly recognized that programs to prevent MTCT must also consider the health of the mother. Antiretroviral prophylaxis regimens, although they prevent MTCT, do not stop progression of HIV infection in the mother. Studies in Africa have shown a 34-fold increase in the risk of death in children, regardless of their HIV infection status, whose mothers have died of HIV infection. Programs such as MTCT-Plus, which is sponsored by private philanthropic foundations and based at Columbia University's Mailman School of Public Health (New York), will work through existing MTCT programs to provide basic care for prevention and/or treatment of HIV-related opportunistic infections and treatment with antiretroviral drugs for HIV-infected mothers and other family members who require therapy. Data from Kenya published in this issue of The Journal of Infectious Diseases show that women with advanced HIV disease (as demonstrated by high virus loads in plasma and breast milk and low CD4+ cell counts) are more likely to transmit HIV through breast milk, suggesting that, in addition to improving maternal health, treatment of such women with antiretroviral therapy may also reduce the risk of transmission through breast milk to their infants. Provision of antiretroviral therapy for HIV-infected, ill individuals may be the most effective inducement for HIV testing in countries with limited resources.
It is easy to become overwhelmed by the enormity of the worldwide perinatal HIV epidemic and the extent of resource and infrastructure needs; however, this cannot be an excuse for inaction. A global collaborative effort and political commitment to extend the benefits that now exist in resource-rich countries to resource-limited countries is needed. Implementation will be challenging. However, the cost of indecision and delay in program implementation is high. Every pediatric HIV infection that is not prevented increases the ultimate economic and social cost to each family, community, and country.
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