Professional Documents
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2012;14:1724
Review
Key content:
r The HIV epidemic continues to be a major challenge to global r Mother to child transmission accounts for 90% of HIV infections r Transmission of HIV from mother to child is largely preventable. r The implementation of interventions to prevent mother to child r Prevention of mother to child transmission of HIV in the
Objectives:
health.
in childhood.
mother to child transmission of HIV in both the developed and developing worlds. r To discuss the challenges in the prevention of mother to child transmission faced by the international community.
Ethical issues:
transmission of HIV has been successful in the developed world. developing world is limited by resources, lack of infrastructure and stigma.
Introduction
The HIV epidemic continues to be a major challenge for global health. The latest figures published by the World Health Organization (WHO)1 show that there are 34 million people living with HIV and 2.02 million of these are children under the age of 15 who require antiretroviral therapy. In 2010 there were 390 000 new HIV infections in children and over 90% of these were acquired by mother to child transmission.1 The HIV epidemic has also had a negative impact on maternal mortality rates, especially in Eastern and Southern Africa.2 Globally, HIV/AIDS is now the leading cause of mortality among women of reproductive age and in several high-prevalence countries, such as South Africa and Zimbabwe, HIV is the leading cause of maternal mortality.3 The challenges in the prevention of mother to child transmission centre on scaling up services to meet the current recommendations of universal antenatal testing in areas of high HIV prevalence and antiretroviral therapy for all HIVpositive pregnant women. Access to antenatal care is variable in resource-limited countries. While 98% of pregnant women in high-income countries report at least one antenatal visit with a skilled health worker, this figure is at most 68% in the developing world (range 28100%).4 In resource-limited
settings only 35% of pregnant women receive an HIV test and 48% of HIV-positive pregnant women receive effective antiretroviral therapy to prevent mother to child transmission, although this is a significant improvement on the 10% in 2004.1, 5 In resource-rich countries, the implementation of multiple evidence-based interventions has reduced mother to child transmission of HIV to very low levels. The mother to child transmission rate in the UK is 1.2% overall and 0.8% in women who have been on antiretroviral therapy for at least the last 2 weeks of their pregnancy.6 To reduce the number of children infected or affected by HIV, the WHO and Joint United Nations Programme on HIV/AIDS (UNAIDS) have proposed a comprehensive approach consisting of four main strategies:5 1 Primary prevention of HIV among women of childbearing age 2 Preventing unintended pregnancies among women living with HIV 3 Preventing HIV transmission from women living with HIV to their infants 4 Providing appropriate treatment, care and support to mothers living with HIV and their children and families.
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This article focuses on the interventions that are effective in addressing the third strategy:
r r r r
antenatal HIV testing antiretroviral therapy during pregnancy, labour and the postnatal period optimal management of labour and delivery support of infant feeding choice.
Increased risk High maternal HIV viral load Low maternal CD4 count Low weight for gestational age Chorioamnionitis Concurrent maternal sexually transmitted infection
We review both the guidance in the UK and guidance from WHO, which is intended primarily for resource-limited countries.
Decreased risk Low maternal HIV viral load Antiretroviral therapy during pregnancy Elective caesarean section Avoidance of breastfeeding
The team will give the positive HIV result, manage the pregnancy, delivery and care of the infant and support the woman and her family through what is often a traumatic time.
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Table 1. Estimated risk of vertical HIV transmission by population and intervention6, 8, 22, 23, 30, 3645, 50, 51 Estimated risk of vertical vertical transmission (%) 2045 1530 6.48.2 12.218 4.19.4 0.56 1 0.1
Population Resource-poor, breastfeeding Resource-poor, non-breastfeeding Resource-rich, non-breastfeeding Resource-poor, breastfeeding Resource-poor, non-breastfeeding Resource-poor, breastfeeding Resource-rich, non-breastfeeding Resource-rich, non-breastfeeding
Intervention None None Elective caesarean section Daily AZT Daily AZT Maternal HAART to 6 months postnatal +/- infant prophylaxis HAART HAART Maternal viral load <50 copies/ml at 36 weeks
These gures are a guide only, based on a review of the relevant literature. AZT = zidovudine; HAART = highly active antiretroviral therapy
lack of health system infrastructure; financial impediments; and social and cultural barriers, including the persistent stigma still attached to the diagnosis of HIV.17 In high-prevalence areas women are more at risk of acquiring primary HIV infection during pregnancy.18 Primary HIV infection is associated with high plasma HIV RNA levels, which increases the risk of mother to child transmission. Some countries, such as South Africa, therefore, have adopted a policy of re-testing pregnant women in the third trimester.19 Serodiscordant couples (in which one partner is initially HIVnegative and the other positive) may account for upwards of 60% of HIV infections in high-prevalence settings in Africa.20 Voluntary testing and counselling of cohabiting couples increases safer sex practices and disclosure of HIV status.21 Testing in the antenatal setting provides an opportunity to offer testing to male partners and for safe sex promotion for serodiscordant couples, in both resource-poor and resourcerich countries.
Table 2. Maternal drug strategies for prevention of mother to child transmission of HIV in the UK (adapted from BHIVA guidelines, 200823 ) Maternal CD4 count (cells/l) <350 Maternal viral load <600010 000 copies/ml HAART >350 START or zidovudine monotherapy + elective caesarean section START
HAART
Antiretroviral therapy
HAART has revolutionised the management of HIV and is the single most important intervention in reducing mother to child transmission in pregnant women. Suppression of maternal HIV viral load improves maternal health outcomes and prevents both in utero, intrapartum and postnatal transmission. Most pregnant HIV-positive women require triple drug therapy, whether initiated for their own health and continued for the rest of their life, or given as a short course to prevent mother to child transmission during the antenatal and postnatal periods. Decisions about maternal antiretroviral therapy and mode of delivery in the UK are based on maternal viral load, but this is often unavailable in resource-poor countries. The BHIVA and the WHO guidelines differentiate pregnant women into those who require HAART for their own health and those who do not.22, 23 The threshold
for starting lifelong HAART has been revised to a CD4 count <350 cells/l. Different treatment strategies are summarised in Table 2 and Table 3. In women who require HAART for their own health, BHIVA recommends that they are treated with a nucleoside reverse transcriptase inhibitor (NRTI) backbone of zidovudine and lamivudine, together with a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor, because this combination has been used most widely in pregnant women.23 However, non-zidovudine-based HAART is increasingly being used in women pre and post-conception and so far there is no evidence of increased risk of maternal HIV viral load at delivery, congenital abnormality or mother to child transmission.24 The WHO guideline also recommends zidovudine and lamivudine as the NRTI backbone, but with nevirapine or efavirenz22 (protease inhibitors are considerably more expensive than NNRTIs and are not widely available in resource-limited countries). In the UK, women who do not require HAART for their own health have two options. Short-term antiretroviral therapy
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Table 3. Maternal drug strategies for prevention of mother to child transmission of HIV in resource-limited countries (adapted from WHO guidelines, 201022 ) Maternal CD4 count (cells/l) <350 (or WHO clinical stages 3 and 4 if CD4 count unavailable) HAART >350 (or WHO clinical stages 1 and 2 if CD4 count unavailable) Option A: Daily antepartum AZT Single dose nevirapine at onset of labour AZT + 3TC during labour and delivery AZT + 3TC for 7 days postpartum Option B: START: commence at 14 weeks and continue until 1 week after end of breast milk exposure
AZT = zidovudine; HAART = highly active antiretroviral therapy; START = short-term antretroviral therapy; 3TC = lamivudine
(START) is a three-drug regimen initiated in the second trimester and discontinued at delivery. UK guidelines suggest a protease inhibitor-based regimen, with a high genetic barrier to resistance and shorter half-life compared with NNRTIs, which minimises the risk of developing drug resistance. Recent data suggest that in women with a plasma viral load >10 000 copies per ml, START may need to be initiated before 20 weeks to achieve an undetectable viral load at delivery.25 If the maternal HIV viral load is <600010 000 copies per ml and the woman does not wish to take START, daily zidovudine initiated at 2428 weeks with an elective caesarean section at 38 weeks is an option.23 This approach minimises the risk of fetal and maternal toxicity and is associated with a <1% risk of transmission.6 The most recent WHO guideline also suggests that women with a CD4 count >350 cells/l can have zidovudine monotherapy.22 See Table 4 for examples of antiretroviral regimens.
The effectiveness of antiretroviral therapy has to be considered alongside potential maternal and fetal toxicity. There are many ethical and practical barriers to conducting trials in pregnant women, but there are over 15 years of experience of antiretroviral therapy in pregnancy and good data on safety and efficacy. Potential pregnancy-specific maternal adverse effects include mitochondrial toxicity with older NRTIs (which are no longer recommended) and a possible increased risk of glucose intolerance with protease inhibitors. Nevirapine is widely used in pregnancy worldwide but can cause rashes and hepatotoxicity; this occurs more frequently in women with a CD4 count >250 cells/l.23 There are conflicting data on whether HAART is associated with preterm delivery26, 27 and research is ongoing. Recent data from the UK and the Republic of Ireland suggest that for every 100 HIV transmissions prevented by HAART, there may be 63 additional preterm deliveries, including 23 at <32 weeks of gestation.28
Table 4. Examples of antiretroviral therapy regimens in pregnancy (adapted from BHIVA and WHO guidelines22, 23 ) BHIVA guidelines Backbone: 2 NRTIs, e.g. tenofovir + emtricitabine or AZT + 3TC Plus: boosted protease inhibitor, e.g. LPV/r, ATZ/r or DRV/r WHO guidelines Backbone: 2 NRTIs, e.g. AZT + 3TC, tenofovir + emtricitabine Plus either: boosted protease inhibitor, e.g. LPV/r Or: NNRTI, e.g. efavirenz Alternative regimen: 3 NRTIs, e.g. AZT + 3TC + abacavir Backbone: 2 NRTIs, e.g. AZT + 3TC, TVF + emtricitabine Plus: NNRTI, e.g. nevirapine or efavirenz
START
HAART
Backbone: 2 NRTIs, e.g. tenofovir + emtricitabine, AZT + 3TC Plus either: NNRTI, e.g. efavirenz , nevirapine (if CD4 <250 cells/l) Or: boosted protease inhibitor, e.g. LPV/r, ATZ/r or DRV/r
AZT = zidovudine; ATZ/r = atazanavir boosted with ritonavir; DRV/r = darunavir boosted with ritonavir; HAART = highly active antiretroviral therapy; LPV/r = lopinavir boosted with ritonavir; NRTI = nucleoside reverse transcriptase inhibitor; START = short-term antiretroviral therapy; 3TC = lamivudine
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There is a theoretical concern that NRTIs could cause mitochondrial toxicity in infants exposed perinatally, but there is limited evidence and further research in this area is required. The Antiretroviral Pregnancy Registry has found no increase in overall risk of birth defects in infants exposed to antiretroviral therapy, including efavirenz, in the first trimester,29 although additional prospective data is required to confirm this.
Infant feeding
Postnatal transmission of HIV occurs due to breastfeeding. Breast milk from HIV-infected mothers contains cell-free HIV RNA and intracellular HIV DNA and both are thought to contribute to transmission.34 The breast milk viral load correlates with the plasma viral load.35 In breastfeeding populations, 2444% of all mother to child transmission of HIV is due to breastfeeding and the cumulative probability of HIV transmission is fairly constant over time and so correlates with duration of breastfeeding.36, 37 Transmission risk is highest with mixed feeding compared with exclusive breast or bottle feeding36, 38 and complete replacement of infant feeding with formula reduces postnatal transmission. Several studies in the developing world show that maternal HAART (or START continued through the breastfeeding period) to suppress maternal viral load and for infant prophylaxis significantly reduces the rate of postnatal transmission of HIV.3945 The estimated cumulative probability of postnatal transmission of HIV in these cohorts is 0.53% at 69 months of age.39, 4244 Breastfeeding reduces infant morbidity and mortality, protects against childhood infections and promotes child spacing. In resource-poor countries mothers often have no access to clean water or formula for safe replacement feeding. Moreover, there can be a stigma attached to replacement feeding, as it can be seen as an indication of HIV infection in both resource-poor and resource-rich countries.41 WHO only advocates replacement feeding if it is acceptable, feasible, affordable, safe and sustainable and recommends that, where this is not the case, women who are HIV-positive breastfeed their infant exclusively until the age of 6 months, then introduce complementary foods and continue breastfeeding until the age of 12 months.46 Mothers who are not eligible for HAART should continue START until all breastfeeding has ceased if resources allow and antiretroviral prophylaxis is recommended for the infant depending on the maternal treatment strategy.22 In the UK exclusive replacement feeding is possible because women have access to formula, clean water, sterilising equipment, counselling and support from postnatal services. There is concern about the unknown risk of exposing uninfected breastfeeding infants to antiretroviral therapy, either through maternal HAART or infant prophylaxis, and the potential for development of viral resistance in HIV-infected infants exposed to antiretroviral therapy who have yet to be diagnosed. This may be a priority in countries where support for formula feeding is readily available. The under-reporting of mixed feeding practices in those encouraged to formula feed is also a concern, as there is no evidence on the risk of transmission with mixed feeding from mothers on HAART. BHIVA and the Childrens HIV Association recently issued guidance, in which they continue to recommend that mothers
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Conclusion
At the United Nations Millennium Summit in 2000, 189 world leaders agreed to meet the Millennium Development Goals. These include: halting the spread of HIV/AIDS, achieving universal access to treatment of HIV/AIDS to those who need it, reducing the under-5s mortality rate by two-thirds and reducing the maternal mortality ratio by two-thirds, by 2015. In June 2011, the Countdown to Zero: Global Plan Towards the Elimination of New HIV Infections in Children by 2015 and Keeping their Mothers Alive set ambitious goals to reduce new childhood infections by 90%, and HIV-related maternal deaths by 50%.48 There has been considerable success in some areas: the coverage of antiretroviral treatment in poorer countries has increased four-fold over 5 years, there has been the first decline in the death rate from AIDS and there has been a significant increase in the proportion of pregnant HIV-positive women getting antiretroviral therapy to prevent mother to child transmission.5, 49 Nevertheless, we are still falling well short of the targets and the HIV/AIDS epidemic remains a global health emergency, with a significant impact on maternal and child mortality and morbidity. Experience in the UK and other resource-rich countries has shown that a universal antenatal HIV screening programme, with appropriate and timely interventions for HIV-positive women, can reduce the risk of mother to child transmission of HIV to very low levels. The challenge of implementing this strategy worldwide is considerable: without access to specialist antenatal care, low-cost drugs and support for exclusive breast or formula feeding, HIV-positive women in the developing world will continue to transmit the virus to their children.
References
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