Update on Preventing Mother-to-child Transmission
Post-partum therapy for moms and infants, plus drug resistance in offspring
by U.S. Centers for Disease Control and Prevention
Editor’s note: The following is a press release from the CDC, with slight changes for writing style.
Two separate clinical studies in Kenya and Malawi investigating the use of antiretroviral drugs (ARVs) to prevent mother-to-child transmission (PMTCT) of HIV through breastfeeding have both shown significant reductions in transmission, paving the way for new prevention approaches in areas where breastfeeding by HIV-positive mothers cannot be avoided. Each study examined a different method of drug delivery: one trial assessed the extended use of ARVs by HIV-positive mothers, and the other investigated the efficacy of ARVs administered to their infants.
Breastfeeding by HIV-positive mothers is a significant source of infection among infants in developing nations—with observed MTCT rates of 25 to 48%. While HIV-positive mothers in the United States and other industrialized countries generally do not breastfeed, in resource-limited settings many HIV-positive mothers have no other option. This is due to a number of factors including the lack of affordable and safe alternate food sources (such as formula and access to clean water), strong cultural traditions of breastfeeding, and reluctance to use formula for fear of being identified as infected with HIV. For HIV-positive mothers who must breastfeed, the World Health Organization (WHO) recommends exclusive breastfeeding for six months, with rapid weaning as soon as an “acceptable, feasible, affordable, sustainable, and safe” replacement feeding option is available, in order to minimize the risk of infection for nursing infants.
Kisumu (Kenya) Breastfeeding Study (KiBS)
Led by CDC’s Timothy Thomas, KiBS is a Phase 2b clinical trial that investigated the extended use of ARVs by HIV-positive mothers in reducing MTCT during breastfeeding. All women in the study were given ARVs (AZT/3TC plus either nevirapine [NVP] or nelfinavir [NFV]) from the 34th week of pregnancy through 6 months post-partum (or beyond if clinically indicated). [Editor’s note: AZT/3TC is Combivir, nevirapine is Viramune, and nelfinavir is Viracept. Nelfinavir is no longer recommended for pregnant women.] During this 6-month post-partum period, the mothers were advised to exclusively breastfeed their newborns according to WHO guidelines. Newborns in the study were also provided standard single-dose nevirapine (SD-NVP) to help prevent HIV transmission which might have occurred during delivery.
Extended maternal use of ARVs was found to dramatically reduce HIV transmission during the breastfeeding period. Of about 500 births (number=497), only 12 newborns (2.4%) were infected by the end of the first week of life (likely in utero or during delivery) and only 15 infants (3.0%) became HIV-positive between 8 days and 12 months of life (via breastfeeding). Researchers found no differences in HIV transmission rates based on the mothers’ CD4 counts or on their specific ARV regimen (among mothers with CD4 counts greater than 200, about half of whom were on regimens with NFV rather than NVP).
These low rates of MTCT are roughly comparable to those found in the U.S. and other industrialized countries where breastfeeding is not practiced, indicating that extended use of ARVs by HIV-positive mothers can closely counter the risk of transmission through breastfeeding in resource-limited settings.
Post-Exposure Prophylaxis for Infants (PEPI-Malawi)
PEPI is a Phase 3 trial sponsored by CDC and NIH and conducted in Blantyre, Malawi, examining the efficacy of administering ARVs to uninfected infants who were breastfed by their HIV-positive mothers according to WHO guidelines. Research was led by Taha Taha (Johns Hopkins University), along with Michael Thigpen (CDC) and Lynne Mofenson (NIH).
More than 3,000 infants were included in the study (number=3,016), and were randomly assigned in equal proportions to one of three groups immediately after birth: (1) standard regimen of SD-NVP plus AZT for 1 week (control group, number=1,003); (2) standard regimen plus daily NVP for 14 weeks (ExtNVP, number=1,016), or (3) standard regimen plus both NVP and AZT daily for 14 weeks (ExtNVP/AZT, number=997).
All women participating in the study were referred to existing HIV care and treatment programs operated by the Malawi Ministry of Health so that they could be started on ARVs if necessary. However, the vast majority of mothers in the trial (85%) were never started on ARVs because their CD4 counts were higher than the level at which treatment would be clinically indicated (in other words, CD4 greater than 200). Of the 15% of mothers who did require treatment, 12% initiated an ARV regimen during the study and were represented in equal proportions among the three arms of the study (11.7% in control group, 12.2% in ExtNVP group, and 11.4% in ExtNVP/AZT group). (The remaining 3% of women with CD4 counts equal to or less than 200 were not started on ARVs due to lack of clinic attendance, loss to follow up, or death.)
By the end of 14 weeks, there were significant differences in HIV infections among the infants (10.0% in control, 3.1% in ExtNVP, and 4.0% in ExtNVP/AZT), which continued over time. By the 9-month endpoint of the trial, 13% of the infants in the control group were infected compared to 7.2% of those in the ExtNVP group and 8.7% in the ExtNVP/AZT group. There were no significant differences in HIV transmission between the ExtNVP and ExtNVP/AZT groups. The trial shows that extended use of ARVs by HIV-exposed infants can substantially reduce HIV transmission during breastfeeding.
Drug resistance as possible key
Both trials demonstrate that ARVs can dramatically reduce MTCT of HIV during breastfeeding—regardless of whether the drugs are provided to HIV-positive mothers (KiBS) or HIV-exposed infants (PEPI). To help determine if one approach might be more beneficial than the other, trial data on potential drug resistance are also being analyzed.
A CDC study of KiBS data (in which mothers were given ARVs) conducted by Clement Zeh and colleagues found that the majority of infants who became infected during the first 6 months of life—the breastfeeding period—developed drug-resistant strains of HIV. Specifically, of the 24 infants in KiBS who became infected by 6 months, two-thirds (67%, number=16) showed genotypic resistance to at least one class of drugs used in the study. Six of 14 babies (43%) whose mothers took the NVP-based regimen developed resistance and all 10 infants whose mothers took the NFV-based regimen developed resistant strains. Researchers believe that sub-therapeutic levels of the ARVs were passed to the infants through breast milk, which contributed to their development of resistance to those drugs.
However, it is important to recognize that the detection of genotypic resistance does not necessarily mean that these infants will be unable to be treated successfully with a particular drug. Genotypic resistance refers to the presence of specific mutations, identified through a DNA analysis, that are known to be associated with resistance to particular classes of drugs. However, before actual resistance could develop, the infants would first need to be started on a specific treatment regimen. It is premature at this point to know the true impact of the genotypic resistance findings from the KiBS trial, though CDC is continuing to closely monitor the HIV-positive children to evaluate their longer-term health outcomes.
Drug resistance data on the HIV-positive infants from the PEPI trial are not yet available. However, CDC and NIH are working closely with researchers from Johns Hopkins University to collect and analyze that information. Results are anticipated in about a year.
Separately, another CDC-sponsored trial in Malawi (Breastfeeding, Antiretroviral, and Nutrition [BAN] trial) is currently conducting a comparison of ARV use by HIV-positive mothers versus HIV-exposed infants during the 6-month breastfeeding period. Those data are expected to be available next year.
Researchers and public health officials are optimistic that the additional data from all three of these trials will help provide important information on how to optimize PMTCT strategies while reducing the risk for developing drug resistance.
In addition, other potential threats to HIV-exposed infants’ health must be considered when assessing optimal PMTCT strategies. For example, at CROI 2007, CDC researchers presented data from three studies showing an elevated risk for severe diarrhea or death among HIV-uninfected infants of HIV-positive mothers who were breastfed according to WHO guidelines. The studies suggested that environmental factors such as inadequate sanitation, unsafe food preparation methods, and lack of clean water contributed to the increased incidence of serious diarrhea.
Translating research into practice
CDC is working with the Ministries of Health in Kenya and Malawi to more fully assess the significance of the trial findings on those nations’ PMTCT strategies. In Kenya, where CDC is already coordinating with health officials to make ARVs available for HIV treatment, the agency is now consulting with the nation’s Ministry of Health, WHO, and PEPFAR to consider making those same drugs available for PMTCT.
In Malawi, the PEPI trial was designed to complement existing national health policies. For example, newborns in Malawi are typically in care for immunizations through the first 14 weeks of life, and are then seen again at 9 months. In addition, the chairman of Malawi’s National AIDS Commission was actively involved in reviewing interim findings from the trial since its inception. CDC and NIH continue to work closely with the Malawi government to help PMTCT of HIV in that country.
As new data become available, CDC will continue to work with policymakers in these and other developing nations, as well as with other international organizations such as WHO, to help identify the most effective approaches for preventing mother-to-child transmission of HIV.
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