Cold Cathode Fluorescence Lamps

Mechanisms, timing and rates

Mother-to-child transmission of HIV can take place in the antepartum, intrapartum and postpartum period and occurs through contact with infected maternal fluids and through breastfeeding (Newell, 1998). Although the placenta acts as an important barrier to HIV, in utero transmission can occur, probably as a result of transfusion of infected blood to the fetus through small tears in the placenta, or through placental disruption, for example by chorioamnionitis (Newell, 1998). Most perinatal HIV transmission occurs around the time of delivery, following exposure of the infant to maternal vaginal secretions and infected blood (Mofenson, 1997; Newell, 1998). Transmission also occurs postnatally through breastfeeding, which accounts for a third to half of perinatal infections in breastfeeding populations (Fowler & Newell, 2002). In an individual patient meta-analysis, the rate of postnatal transmission after four weeks of age was estimated to be 8.9 per 100 child-years of breastfeeding (The Breastfeeding and HIV International Transmission Study (BHITS) Group, 2004). In the absence of prophylactic interventions, MTCT rates for HIV are estimated to range from 13% to 32% in resource-rich countries and from 25% to 48% in resource- poor countries (Dabis et al., 1993), with differences attributed mainly to variation in breastfeeding duration.

Factors shown to be associated with MTCT include maternal plasma HIV RNA viral load, CD4 count, mode of delivery, duration of ruptured membranes and gestational age at delivery (European Collaborative Study, 1996b; Stratton et al., 1999; Thorne & Newell, 2004b). HIV RNA viral load is the strongest predictor of MTCT, with a doubling of risk for each log10 increase in viral load (Cooper et al., 2002; European

Collaborative Study, 1999). Low CD4 count is also associated with an increased risk of transmission (European Collaborative Study, 1996b; European Collaborative Study, 2001). Differences in transmission by mode of delivery were first detected in observational studies in the early 1990s, in which elective caesarean section was found to be associated with a reduced risk of transmission compared with vaginal delivery (European Collaborative Study, 1994; European Collaborative Study, 1999; Moodley et al., 1994). This was confirmed in both a randomised clinical trial and a meta-analysis, which demonstrated a more than 50% reduction in transmission associated with planned pre-labour caesarean section (The European Mode of Delivery Collaboration, 1999; The International Perinatal HIV Group, 1999). In a meta-analysis, which included mostly untreated women, duration of ruptured membranes was associated with a 2% increase in transmission for each additional hour of ruptured membranes (The International Perinatal HIV Group, 2001).

Prematurity was found to be a risk factor for transmission in early studies of women who were mostly untreated or on zidovudine alone (European Collaborative Study, 1996b; European Collaborative Study, 1999; Kuhn et al., 1999). However, it is less clear whether premature delivery remains an independent predictor of transmission in HAART-treated women, particularly if viral load is suppressed (European Collaborative Study, 2005d; Warszawski et al., 2008).

The primary intervention for reducing MTCT is ART, which is administered to the mother during pregnancy and delivery to reduce plasma HIV RNA viral load, and to the neonate as prophylaxis (Newell & Thorne, 2004). Elective caesarean section delivery and formula feeding are also now standard practice in resource-rich settings (BHIVA/CHIVA, 2008). This combined prevention approach led to overall declines in MTCT rates in resource-rich countries from around 20-25% to around 1-2% in the

late 1990s (Centers for Disease Control and Prevention, 2006; Cooper et al., 2002; Duong et al., 1999; European Collaborative Study, 2001), and rates of 1% or less have been reported in recent years (Dorenbaum et al., 2002; European Collaborative Study, 2005d; Peters et al., 2008; Warszawski et al., 2008). Widespread use of HAART has meant that the majority of women achieve low or undetectable HIV RNA viral load by the time of delivery, and it is now unclear whether planned caesarean section delivery confers any additional benefit for these women. Elective caesarean section may carry a higher risk of postpartum morbidity than vaginal delivery (Read & Newell, 2005), although possibly not in women on HAART (Duarte et al., 2006). Since 2005, guidelines have suggested that women on HAART who have uncomplicated pregnancies and an undetectable viral load may attempt a vaginal delivery, although there was limited evidence to support this

recommendation. There is also uncertainty about the role of obstetric factors, such as duration of ruptured membranes and premature delivery, in relation to the risk of MTCT among women achieving viral suppression (European Collaborative Study, 2005d; Jamieson et al., 2007; Newell & Thorne, 2004).

Antiretroviral therapy in pregnancy

In 1994, the beneficial effects of zidovudine in pregnancy were first demonstrated in the AIDS Clinical Trial Group (ACTG) 076 trial of women with CD4 counts above 200 cells/µl, in which zidovudine was administered antenatally, starting between 14 and 34 weeks gestation (median 28 weeks), intravenously in labour, and orally to the baby for the first six weeks of life (Connor et al., 1994). The transmission rate was two thirds lower in the intervention (8%) than in the control arm (25%). The benefits of zidovudine have also been demonstrated in a number of observational studies in

non-breastfeeding populations (Cooper et al., 2002; European Collaborative Study, 2001; Kind et al., 1998; Mayaux et al., 1997). Subsequently, the addition of

lamivudine, another NRTI, to the 076 protocol was shown to further reduce the transmission rate to 1.6% in the Agence Nationale de Recherche sur le Sida (ANRS) 075 trial, but this was overshadowed by concerns about adverse events and drug resistance (Mandelbrot et al., 2001). There have been no clinical trials of HAART in pregnancy, partly due to the low transmission rates (<2%) achieved with

combination therapy (Dorenbaum et al., 2002), but it has been shown in

observational studies to have a greater effect on transmission rates than zidovudine alone. In the Women and Infants Transmission Study of around 1500 women in the United States (US), MTCT occurred in 10% of those taking zidovudine, 4% of those receiving dual therapy, and 1.2% of those on HAART (Cooper et al., 2002). In developed countries, HAART is now the standard of care for treatment in pregnancy, with transmission rates around 1% (European Collaborative Study, 2005d;

Warszawski et al., 2008).

In recent years, a substantial proportion of women have been conceiving on HAART (European Collaborative Study, 2005a; Watts et al., 2007). Current recommendations suggest that normal treatment should be continued after conception, with the

exception of efavirenz (see page 42) (BHIVA/CHIVA, 2008; Perinatal HIV Guidelines Working Group, 2008). The majority of women diagnosed for the first time in pregnancy initiate treatment during the second or third trimester of

pregnancy. Some women may already have depleted CD4 cell counts at diagnosis and require HAART for their own health, but for those diagnosed at an earlier stage of disease and initiating treatment purely for MTCT prophylaxis, less potent

used for treatment of HIV-infected adults or children, it remains an option for MTCT prevention. Early studies suggested that when used in combination with elective caesarean section and no breastfeeding, zidovudine could reduce the risk of MTCT to below 1% (European Mode of Delivery Collaboration, 1999). The British HIV Association (BHIVA) Guidelines currently support this strategy for women who do not need HAART for their own health, have a pre-treatment viral load below 6000- 10,000 copies/ml and are willing to deliver by planned pre-labour caesarean section (BHIVA/CHIVA, 2008). Recommendations in the US are more cautious, suggesting that zidovudine monotherapy should only be considered in women with viral load <1000 copies/ml (Perinatal HIV Guidelines Working Group, 2008). There are

limited data on the selective use of zidovudine monotherapy for preventing MTCT in women who do not require HAART, and no trials have addressed the relative

efficacy of this approach compared with short-course HAART. In an audit that included 85 women who received zidovudine monotherapy in pregnancy, only a quarter had started HAART following pregnancy (at a median of 28 months follow- up), and they were just as likely to have responded to treatment as those who had received short-course HAART (Martin et al., 2006).