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Triple antiretroviral prophylaxis during pregnancy and breastfeeding is safe and reduces the risk of HIV transmission to infants. pdf attached
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Download the PDF here
The Lancet Infectious Diseases, Early Online Publication, 14 January 2011
"Breastfeeding is essential for child health and development in low-resource settings but carries a significant risk of transmission of HIV-1, especially in late stages of maternal disease. We aimed to assess the efficacy and safety of triple antiretrovirals compared with those of zidovudine and single-dose nevirapine for prevention of MTCT during pregnancy and breastfeeding for pregnant women infected with HIV-1 who had CD4 cell counts of 200-500 copies per μL.........From June, 2005, to August, 2008, 882 women were enrolled, 824 of whom were randomised and gave birth to 805 singleton or first, liveborn infants. The cumulative rate of HIV transmission at 6 weeks was 3·3% (95% CI 1·9-5·6%) in the triple antiretroviral group compared with 5·0% (3·3-7·7%) in the zidovudine and single-dose nevirapine group, and at 12 months was 5·4% (3·6-8·1%) in the triple antiretroviral group compared with 9·5% (7·0-12·9%) in the zidovudine and single-dose nevirapine group (p=0·029). The cumulative rate of HIV transmission or death at 12 months was 10·2% (95% CI 7·6-13·6%) in the triple antiretroviral group compared with 16·0% (12·7-20·0%) in the zidovudine and single-dose nevirapine group (p=0·017). In infants whose mothers declared they intended to breastfeed, the cumulative rate of HIV transmission at 12 months was 5·6% (95% CI 3·4-8·9%) in the triple antiretroviral group compared with 10·7% (7·6-14·8%) in the zidovudine and single-dose nevirapine group (p=0·02)."
"Ensuring an undetectable viral load by the time of delivery and during breastfeeding is the aim of maternal antiretroviral prophylaxis but cannot be achieved in all circumstances. Both duration of antenatal triple antiretroviral prophylaxis and baseline viral load were significantly associated with undetectable viral load at delivery in Kesho Bora in women receiving triple antiretroviral prophylaxis. However, with 8 weeks of prophylaxis viral load remained detectable in almost 30% of women."
"Pregnant women with WHO stage 1, 2, or 3 HIV-1 infection who had CD4 cell counts of 200-500 cells per μL were enrolled at five study sites in Burkina Faso, Kenya, and South Africa to start study treatment at 28-36 weeks' gestation. Women were randomly assigned (1:1) by a computer generated random sequence to either triple antiretroviral prophylaxis (a combination of 300 mg zidovudine, 150 mg lamivudine, and 400 mg lopinavir plus 100 mg ritonavir twice daily until cessation of breastfeeding to a maximum of 6·5 months post partum) or zidovudine and single-dose nevirapine (300 mg zidovudine twice daily until delivery and a dose of 600 mg zidovudine plus 200 mg nevirapine at the onset of labour and, after a protocol amendment in December, 2006, 1 week post-partum zidovudine 300 mg twice daily and lamivudine 150 mg twice daily). All infants received a 0·6 mL dose of nevirapine at birth and, from December, 2006, 4 mg/kg twice daily of zidovudine for 1 week after birth. Patients and investigators were not masked to treatment. The primary endpoints were HIV-free infant survival at 6 weeks and 12 months; HIV-free survival at 12 months in infants who were ever breastfed; AIDS-free survival in mothers at 18 months; and serious adverse events in mothers and babies. Analysis was by intention to treat."
Three-Drug ART Reduces HIV Transmission Risk
medpagetoday
January 13, 2011
In many parts of the world, the standard for preventing mother-to-child transmission of HIV is a short course of a single anti-retroviral drug.
But a large randomized trial in Africa showed that full-scale anti-retroviral therapy with three drugs reduces the risk of passing on the virus even further, researchers reported online in The Lancet.
A year after birth, children born to mothers given triple-drug therapy were 43% less likely to have HIV than children of women given standard prophylaxis, according to Timothy Farley, PhD, of the World Health Organization, and colleagues in the Kesho Bora Study Group.
Action Points
* Note that this study indicates that triple-anti-retroviral prophylaxis during pregnancy and breast feeding is safe and reduces the risk of HIV transmission to infants significantly when compared with standard treatment with single therapies.
The results of the study (and others) were the basis of a 2009 decision by the WHO to revise its international guidelines for anti-retroviral use by pregnant and breast-feeding women. The agency now recommends maternal triple prophylaxis -- starting from the second trimester of pregnancy until all exposure to breast milk has ended -- even if the woman is not yet eligible for the therapy for her own health.
The Kesho Bora study -- the name means "a better future" in Swahili -- randomly assigned 824 women with a serum CD4-positive T-cell count of between 200 and 500 cells per microliter to get standard or triple therapy.
The standard therapy was zidovudine (AZT) twice daily until delivery, with a dose of zidovudine plus nevirapine (3TC) at the onset of labor. After a protocol amendment in December 2006, women were also given a week of postpartum zidovudine and lamivudine twice daily.
The triple therapy was zidovudine, lamivudine, and ritonavir-boosted lopinavir (Kaletra) twice daily until the end of breastfeeding (to a maximum of 6.5 months after delivery).
All infants were given 0.6 milliliters of nevirapine at birth and -- after the 2006 protocol amendment -- zidovudine twice a day for a week after birth.
The researchers found:
* At six weeks, the cumulative rate of HIV transmission was 3.3% in the triple therapy group and 5% in the single-therapy arm, a difference that was not significant.
* On the other hand, at 12 months the rates were 5.4% and 9.5%, respectively, and the difference was significant at P=0.029.
* The relative risk reduction was 43% -- based on 21 events among 333 infants in the triple-therapy group and 37 among the 305 babies in the single-therapy arm.
* Among babies born to mothers who said they intended to breast feed, the relative risk reduction was 48%, significant at P=0.02.
The incidence of both laboratory and serious clinical adverse events was similar between the groups, the researchers reported.
The study provides evidence that triple therapy might be a universal approach that could be used at the population level, according to Renaud Becquet, PhD, and Didier Ekouevi, MD, PhD, both of University Victor Segalen Bordeaux 2 in Bordeaux, France.
Such a strategy would improve maternal survival and lower the risk of HIV transmission to male partners, they argued in an accompanying comment article.
But it would also raise a difficult question: when to stop the therapy in women who do not yet need it for their own health, they argued. More research is needed to help decide "whether, how, and when to stop maternal triple-anti-retroviral prophylaxis after breast feeding cessation," they concluded.
One approach is simply to put all pregnant HIV-positive women permanently on triple therapy, as is now being tried in Malawi, they noted. But that would require both money and human resources that are not readily available in many countries, they argued.
Triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis during pregnancy and breastfeeding for prevention of mother-to-child transmission of HIV-1 (Kesho Bora study): a randomised controlled trial - pdf attached
The Lancet Infectious Diseases, Early Online Publication, 14 January 2011
The Kesho Bora Study Group
The rates of late postnatal HIV infections (after age 6 weeks) were 2·2% (95% CI 1·1-3·9%) in the triple antiretroviral group and 4·7% (2·9-7·3%; p=0·054) in the zidovudine and single-dose nevirapine group (relative risk reduction 53%), and only occurred in infants who were ever breastfed (data not shown). In both groups, the risk of late transmission after birth was associated with longer breastfeeding (median duration 22·4 [IQR 11·1-28·7] weeks in infants infected after birth compared with 13·7 [0·7-22·3] weeks in uninfected infants; p=0·001) and higher plasma viral load at delivery (median 3·3 [2·6-3·9] vs 2·5 [0·0-3·4] log10 copies per mL; p=0·006), but not with mode of breastfeeding (exclusive up to 3 months vs mixed; p=0·73; data not shown).
Triple antiretroviral prophylaxis was not associated with significant increases in antiretroviral-related serious adverse events in mothers or their babies compared with zidovudine and single-dose nevirapine prophylaxis. Further analyses of the effect of triple antiretroviral prophylaxis on maternal health outcomes such as emergence of drug resistance and HIV disease progression are underway. Follow-up of mothers to 18-24 months (to be reported elsewhere) will provide important information.
Maternal median CD4 cell counts were higher in the triple antiretroviral group than the zidovudine and single-dose nevirapine group at delivery, and at 6 months and 12 months (table 2). At delivery, the proportion of women with undetectable viral load was over two-times higher in the triple antiretroviral group than in the zidovudine and single-dose nevirapine group (p<0·0001; table 4). In the triple antiretroviral group, women with a shorter duration of treatment with antiretrovirals before delivery and those with higher viral load at enrolment were less likely to have undetectable viral load at delivery (table 4). In this group, the protocol amendment to initiate prophylaxis as soon as possible after 28 weeks instead of 34 weeks gestation increased the median duration of prophylaxis before delivery (7·7 weeks vs 5·0 weeks, p<0·0001) and the proportion of women with undetectable viral load at delivery (p=0·002; table 4). In an exploratory multivariate analysis, lower viral load at enrolment (p<0·0001) and longer duration of antiretroviral use before delivery (p=0·003) were significantly associated with undetectable viral load at delivery, after adjustment for centre in the triple antiretroviral group. In the zidovudine and single-dose nevirapine group, only lower viral load at enrolment was predictive of undetectable viral load at delivery after adjustment for centre (p<0·0001).
In the triple antiretroviral group, fewer infants were infected with HIV at 12 months (one had only one diagnostic assay) than in the zidovudine and single-dose nevirapine group (four only had one diagnostic assay; table 6; figure 2). The 12-month cumulative HIV infection rate was lower in the triple antiretroviral group than in the zidovudine and single-dose nevirapine group (p=0·029)-a relative risk reduction of 43%. The risk was not significantly different between groups at birth (p=0·52) or at 6 weeks of age (p=0·24). The number of infants infected after 6 weeks (when all transmissions are attributable to breastfeeding) but before 6 months after birth (end of breastfeeding with antiretroviral prophylaxis) was six in the triple antiretroviral group and 13 in the zidovudine and single-dose nevirapine group. The rates of infant HIV infection or death at 12 months were lower in the triple antiretroviral group than in the zidovudine and single-dose nevirapine group (p=0·017). Among the 75% of women who intended to breastfeed at the time of randomisation, of whom 571 of 597 (96%) actually initiated breastfeeding, cumulative rates of transmission at 12 months were lower in the triple antiretroviral group than in the zidovudine and single-dose nevirapine group (p=0·02; table 6); the relative risk reduction was 48%.
When stratified by CD4 count at enrolment (prespecified secondary objective), there was a significant difference at 12 months between the triple antiretroviral group and the zidovudine and single-dose nevirapine group when the CD4 count was less than 350 cells per μL (p=0·03; 48% risk reduction) but not when the CD4 count was 350 cells per μL or higher (p=0·33; 34% risk reduction; table 6). The number of infections averted was 12 in infants born to mothers with CD4 counts of less than 350 cells per μL versus four in those born to mothers with counts of 350-500 cells per μL. In infants born to mothers with CD4 counts less than 350 cells per μL there were four infections between 6 weeks and 6 months in the triple antiretroviral group versus nine in the zidovudine and single-dose nevirapine group, a 56% reduction. The risk of transmission was low in both groups when women had undetectable plasma viral loads at delivery, with a cumulative rate at 12 months of 2·7% in both groups (table 6). In an exploratory univariate and multivariate analysis, the only factor from the mother and infant characteristics (Table 1, Table 2, Table 5) significantly associated with peripartum transmission was detectability of virus at delivery (p=0·03; data not shown).
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