JAC Advance Access originally published online on August 25, 2009
Journal of Antimicrobial Chemotherapy 2009 64(5):895-900; doi:10.1093/jac/dkp303
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Leading articles |
The safety of highly active antiretroviral therapy for the HIV-positive pregnant mother and her baby: is ‘the more the merrier’?
Section of Infectious Diseases, Faculty of Medicine, Imperial College, Norfolk Place, London W2 1PG, UK
* Corresponding author. Tel/Fax: +44-207594-3910; E-mail: f.martin{at}imperial.ac.uk
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Abstract |
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 Top Abstract IntroductionTeratogenicityMitochondrial toxicityAdverse outcomes of pregnancy...Concluding commentsFundingTransparency declarationsReferences |
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Highly active antiretroviral therapy (HAART) is frequently indicated for pregnant women both for maternal health and for prevention of mother-to-child HIV transmission, which can be reduced to <1%. Prospective data and large cohort studies have not found any evidence that antiretroviral therapy significantly increases the risk of congenital malformation. Nucleoside analogue reverse transcriptase inhibitors (NRTIs) are, to varying degrees, toxic to mitochondria, and molecular and clinical evidence of mitochondrial toxicity has been reported, albeit rarely, in NRTI-exposed but HIV-uninfected children. However, with NRTI-based fully suppressive antiretroviral therapy this effect was not seen. Although conflicting observational data have been reported, an increased risk of pre-term delivery with HAART compared with zidovudine monotherapy remains a concern.
Keywords: HAART , vertical transmission , pre-term delivery
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Introduction |
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TopAbstractIntroductionTeratogenicityMitochondrial toxicityAdverse outcomes of pregnancy...Concluding commentsFundingTransparency declarationsReferences |
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Several interventions including zidovudine monotherapy, single-dose nevirapine, highly active antiretroviral therapy (HAART), pre-labour planned caesarean section (PLCS) and not breast feeding have been shown to effectively reduce HIV mother-to-child transmission (MTCT). Recent data from the UK and Ireland show that, when these are applied appropriately, transmission rates as low as 0.1% are achievable.1 However, optimal strategies for different settings and patients' preferences and needs remain to be defined. With success in prevention, the focus of research is increasingly on safety. Is more always better and safer than less and are all combinations equal in pregnancy?
This article aims to summarize and contextualize the latest data on the safety of antiretroviral therapy (ART) in pregnancy and discuss the current controversies.
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Teratogenicity |
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TopAbstractIntroductionTeratogenicityMitochondrial toxicityAdverse outcomes of pregnancy...Concluding commentsFundingTransparency declarationsReferences |
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No increase in birth defects following in utero ART exposure during organogenesis has been detected by the antiretroviral pregnancy registry (APR) from prospective data on 4329 live births to July 2008.2 Although zidovudine has been associated with an increased risk of hypospadias in the Women and Infants Transmission Study (WITS)3 and efavirenz is the only ART classified by the US FDA in Class D on the basis of retrospective case reports of spina bifida and Dandy–Walker syndrome, the only compound for which an overall increase in congenital abnormalities has been seen in the prospective data set of the APR is didanosine.2 However, no particular abnormality has been reported for didanosine and it remains one of the 12 older ARTs for which there are sufficient data to exclude a 2-fold increase in congenital malformations.
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Mitochondrial toxicity |
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TopAbstractIntroductionTeratogenicityMitochondrial toxicityAdverse outcomes of pregnancy...Concluding commentsFundingTransparency declarationsReferences |
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Nucleoside analogue reverse transcriptase inhibitors (NRTIs) are known to cause mitochondrial DNA (mtDNA) depletion with a range of end organ effects. Deaths from lactic acidosis have been reported in pregnant women taking didanosine with stavudine,4 and this combination is no longer recommended for pregnant women and is rarely ever prescribed in general. However, infant deaths and morbidity from mitochondrial toxicity were reported in the French cohort following perinatal exposure to zidovudine alone or taken with lamivudine in HIV-uninfected children.5 Although other cohort studies have not replicated these findings mtDNA depletion has been reported in HIV-negative infants, born to HIV-positive mothers, for up to 2 years and this was more marked in those exposed to zidovudine monotherapy.6 However, in a prospective cohort study of mothers mostly initiating HAART with NRTIs and an HIV protease inhibitor (PI), no significant difference in the lymphocyte mtDNA/nuclear DNA ratio was detected in these women compared with HIV-uninfected controls (P > 0.25). Furthermore a significant rise in mtDNA was seen in all women (P = 0.031) over time, and the highest mtDNA levels were in cord blood (P < 0.001).7 Data from the same group show increased blood mtDNA levels in infants with antenatal HAART exposure compared with HIV-unexposed, ART-unexposed control infants and that mtDNA further increased during neonatal exposure to zidovudine, whereas mtDNA gene expression in these infants was decreased.8
Thus, mitochondrial toxicity appears to be a feature of HIV infection per se that may be exacerbated by zidovudine monotherapy. Therapy that fully suppressed HIV replication reduced this effect, and this may be true even if the therapy includes components that are potentially toxic to mitochondria, such as zidovudine. In this regard, more appears to be better, and it is interesting to note that the data from France on clinically important manifestations of mitochondrial depletion have not been replicated, perhaps because increasingly mothers and babies are exposed to HAART that fully suppresses HIV replication. Analysis of data from 984 HIV-exposed but uninfected infants of which two had suspected and one proven mitochondrial dysfunction revealed there to be an association between this dysfunction and earlier calendar year and higher maternal HIV load.9
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Adverse outcomes of pregnancy (summarized in Table 1) |
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TopAbstractIntroductionTeratogenicityMitochondrial toxicityAdverse outcomes of pregnancy...Concluding commentsFundingTransparency declarationsReferences |
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An increase in pre-term delivery (PTD; <37 weeks) with HAART was first reported by the Swiss,10 and has since been noted in the European Collaborative Study (ECS),11,12 the UK cohort,13 and Italian,14 Dutch15 and German/Austrian16 studies. The relative risk (RR) varies but the effect seems to be more marked with severe PTDs (<32 or 34 weeks). Some studies report a greater effect with PIs than with nevirapine and some with first trimester rather than later first exposure. Other factors associated with PTD were increasing maternal age, CD4+ T-lymphocyte cell count <200 cells/mm3 and injecting drug use. The ECS logistic regression analysis of data from 2279 mother–infant pairs demonstrated that, compared with zidovudine monotherapy, the adjusted odds ratio (AOR) for PTD with HAART was 1.88 if started antenatally and 2.05 if commenced prior to pregnancy.12
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In a meta-analysis of 13 cohorts performed by the US CDC, HAART compared with no therapy was not associated with PTD, but PI-based compared with non-PI-based HAART (OR 1.24) and HAART started prior to or during the first trimester (OR 1.71) were associated with PTD.17
In a UK centre, 14.2% of the 211 deliveries were pre-term, of which the majority (9%) were at <34 weeks, and there were 1.4% stillbirths. Sixty-seven percent of all PTDs occurred in the mothers (40%) who started HAART during pregnancy. In a multivariant analysis, initiating HAART during pregnancy was the only significant indicator for PTD (OR 5.03). PTD was associated with PI-based regimens more than with non-nucleoside reverse transcriptase inhibitors (NNRTIs), but rates with zidovudine monotherapy (5.7%) were comparable to those in the general population (6–8%).18
Data from the national UK database on 5462 pregnancies show that, compared with zidovudine monotherapy given regardless of maternal immune status in the pre-HAART era (pre-1998), HAART was associated with a 1.4- and 2-fold increase in PTD at <37 weeks (AOR 1.40) and <32 weeks (AOR 2.16), respectively, after adjusting for injecting drug use, HIV symptoms and CD4 count.19 These data suggest that the low PTD rates seen with zidovudine monotherapy in recent years cannot be completely explained by selection bias, in which only women with good immune function and low HIV load are offered this intervention, as has been the practice in the UK since 1997.
In an Italian surveillance study the multivariate analyses of 419 deliveries showed not only an increase in PTDs with PI-based HAART initiated in the second and third trimester but also independently with hepatitis C virus co-infection [AOR 2.9, 95% confidence interval (CI) 1.6–5.4].20
Some data from North and South America appear to contradict these findings. Thus in the Pediatric Spectrum of HIV Disease cohort (1989–2004) PTD decreased from 35% to 21% whilst ART exposure during pregnancy increased over the same period from 2% to 84%.21 Analysis of data from seven clinical studies between 1990 and 1998 found no difference in risk between the 1143 mothers who received no treatment (PTD rate 17%) and the 1590 treated with zidovudine monotherapy (PTD rate 16%). Furthermore, no increased risk, compared with monotherapy, was seen with HAART (n = 533, AOR 1.08), but only 137 mothers were exposed to a PI-based regimen, of whom only 66 had commenced HAART prior to gestational week 28.22 Similarly, in the WITS (1990–1998), analysis of 2453 pregnancies did not reveal an association of HAART with PTD despite a PTD rate of 18%. However, an undisclosed number of mothers initiated treatment after 32 weeks gestation, which might have diluted any effect of HAART on PTD.23
Miami, one of the collaborating sites of the aforementioned WITS, has since 1995 provided all mothers with HAART whilst reserving PI-based regimens for mothers with advanced disease. In their single-centre analysis an association between PTD <37 weeks (but not <32 weeks) and HAART (n = 507), but especially PI-based regimens (n = 134), compared with zidovudine monotherapy (n = 492) was found. This was most apparent when the PI-based regimen was started after 27 weeks, with 41% of deliveries pre-term. The only other predictors of PTD were a history of PTD (AOR 3.4, 95% CI 2.3–5, P = 0.0001) and duration of ART <10 weeks (AOR 2.2, 95% CI 1.6–3, P = 0.0001). There was no increased association between any specific PI and PTD. Nelfinavir was the most commonly used PI (n = 86).24
Multivariable analyses of data from Latin America and the Caribbean on 681 HIV-positive pregnant women delivering showed no correlation between PI-based HAART (n = 330) and small for gestational age (SGA; AOR 1.5) or PTD (AOR 1.1) when compared with those receiving monotherapy or dual therapy (n = 93). Neither could an association be established between short-term or continuous therapy with SGA or PTD. However, both were more common in Brazil and associated with pre-eclampsia (SGA: AOR 17.5, 95% CI 4.6–66.1; PTD: AOR 19.8, 95% CI 5.2–75.2), maternal diabetes (SGA: AOR 4.0, 95% CI 1.2–13.6; PTD: AOR 7.4, 95% CI 2–27) and low maternal weight (SGA: AOR 3.5, 95% CI 1.9–6.2; PTD: AOR 3.6, 95% CI 1.8–7.2). The shortcomings of this study are the lack of data on the background rate of SGA and PTD for HIV-negative mothers and stratification by timing of prophylactic HAART and the exclusion of all stillbirths.25
A single-centre study (n = 696) from Rio de Janeiro, Brazil (1996–2006) associated PTD (AOR 5) and SGA (AOR 3.6) with pre-conception HAART (n = 108) compared with HAART started after the first trimester (n = 205). PTD was also associated with high HIV viral load (VL) >10 000 copies/mL antenatally and at delivery (AOR 5.1, 95% CI 1–30.8) and SGA with hypertension (AOR 3.8, 95% CI 2.24–8.26). However, at delivery 38% of the VL data were missing and only 44%, equally distributed between the monotherapy/dual therapy (n = 79) and HAART (n = 89), had achieved an undetectable VL. There was no statistical difference between PI-based and NNRTI-based regimens due to small numbers. However, zidovudine monotherapy (n = 179) was not associated with adverse pregnancy outcomes.26
In the pre-HAART era, HIV infection was associated with low rates (0.8%) of pre-eclampsia.27 A restoration of risk of pre-eclampsia with HAART (11%) compared with no ART (0%) but not with zidovudine monotherapy (1%) was reported from the UK in 200228 and supported by data from Spain (1985–2003) of a sharp rise in pre-eclampsia and fetal death in HIV-infected pregnant mothers (n = 472) after the introduction of HAART in 2001. Pre-eclampsia was associated with pre-conception HAART (AOR 8.9, 95% CI 1.7–45.5) as was pre-eclampsia and/or fetal death (AOR 5.6, 95% CI 1.7–18.1).29
Until recently the experience with HAART in pregnancy has mostly been reported from health-resource-rich settings with access to neonatal intensive care. As the ART programme rolls out, large numbers of HIV-positive pregnant women are now treated with HAART in developing regions where the impact of PTD on infant morbidity and mortality is potentially greater.
In a cohort treated with NNRTI-based HAART in Bangkok, PTD occurred in 18.5% of mothers treated with nevirapine,30 which is similar to the rate reported with HAART in Europe and North America.23
In West Africa, the Ditrame Plus/MTCT Plus study showed an increase in the rate of low birth weight babies with nevirapine-based HAART compared with zidovudine monotherapy (22.3% versus 12.4%, P = 0.02), even though both were initiated at >34 weeks gestation. In a multivariate analysis (n = 309), HAART was independently associated with low birth weight (OR 2.53). No impact on 1 month survival in HIV-positive infants of low birth weight was seen, but data on the survival of HIV-uninfected infants were not presented.31
An increased risk of SGA and stillbirth was reported from Southern Africa with continuation (SGA: AOR 1.8, stillbirth: AOR 2.0) as well as initiation of HAART (SGA: AOR 2.8, stillbirth: 3.7). Hypertensive complications at birth were significantly higher amongst women who continued pre-existing therapy (n = 127) compared with those who initiated HAART (n = 112) during pregnancy (9% versus 4%, P = 0.02): stillbirth (OR 7.2, 95% CI 3.8–13.7), PTD (OR 1.7, 95% CI 1.3–2.4) and SGA (OR 2.1, 95% CI 1.4–3.0). However, most new HAART was initiated after 28 weeks of gestational age and therefore probably too late to cause a significant increase in severe PTDs.32
In summary, concerns remain that HAART may be associated with severe PTD whereas none of the aforementioned studies associates zidovudine monotherapy with adverse pregnancy outcomes in either the pre-HAART or the HAART eras. Therefore, in selected cases, more (ART) may not be better; however, there are national and international differences in data and opinion. Possible explanations for these differences include variable background risks for PTD and different antiretroviral prescribing practice that may have changed over time. Clearly the timing of therapy during pregnancy will influence the likelihood of an association with PTD especially if a significant proportion of women included in the studies started therapy late. It may also be important to discriminate between women who change therapy during pregnancy due to poor viral control and those who have fully suppressed HIV. The importance of clarifying this controversy cannot be underestimated. PTD, especially before 32 weeks, is associated with increased neonatal morbidity and requires intensive resources. However, HIV infection per se is associated with obstetric complications and in many cases needs to be treated to preserve maternal health. A recent report from Botswana reminds us that HIV infection is associated with premature delivery (RR = 1.38, 95% CI 1.23–1.55), neonatal death (RR = 1.50, 95% CI 1.00–2.25), low birth weight (RR = 1.55, 95% CI 1.34–1.78), very low birth weight (RR = 1.42, 95% CI 1.07–1.88) and stillbirth (RR = 1.39, 95% CI 0.98–1.98).32
Rolling out HAART will reduce HIV MTCT but transmission rates with zidovudine monotherapy and single-dose nevirapine are already low (1.9%),33 and in selected populations zidovudine monotherapy accompanied by PLCS virtually eliminates transmission (0–1%).1 Some authors have been concerned that zidovudine monotherapy, even when prescribed to selected mothers to prevent MTCT, will lead to the development of thymidine-associated mutations and subsequent treatment failure.34 However, there are no data to suggest that this happens and, when sought, such mutations have not been found in this setting.35
Current UK treatment guidelines recommend HAART for all patients with CD4 
350 cells/mm3, advise against efavirenz-based HAART in pregnancy and reserve nevirapine-based HAART for mothers with a CD4 count <250 cells/mm3.36 Therefore, very soon most HIV-positive pregnant mothers who need HAART, either for themselves or for a short course during pregnancy due to high VL, will be offered a PI-based regimen. Careful examination of PTD rates and any associated morbidity or mortality is necessary as HAART is increasingly also prescribed to pregnant women who do not have access to neonatal intensive care. If the European experience is replicated and an association with PI-based therapy confirmed, strategies to minimize the risk will be needed. Whilst the data from the Strategies for Management of Anti-Retroviral Therapy (SMART) study of an increased risk of inflammatory and infection-related events in adults receiving CD4-guided episodic therapy cause some concern,37 to date there are no data on the effects of repeated short courses of HAART, to prevent MTCT, in otherwise healthy HIV-positive pregnant women.
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Concluding comments |
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TopAbstractIntroductionTeratogenicityMitochondrial toxicityAdverse outcomes of pregnancy...Concluding commentsFundingTransparency declarationsReferences |
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With HIV-1 MTCT rates falling, due to a variety of antiretroviral interventions and PLCS, comparison of the rates of adverse events between interventions becomes increasingly important. In this article we have focused on three areas of concern and controversy: teratogenicity with ART; mitochondrial toxicity with NRTIs; and adverse pregnancy outcomes with HAART.
There is no strong evidence of teratogenicity with ARTs but data are sparse for the new drug classes. Whilst concerns relating to mitochondrial toxicity are diminishing and better suppression of HIV replication may be protective, this is not the case with PTD. Paradoxically the recent trend to initiate HAART earlier in women perceived to be at risk of PTD or with high VL (e.g. at 20–32 weeks36 rather than late in the second trimester38) could aggravate the risk of severe PTD whilst striving to ensure full viral suppression before delivery.
At this stage of antiretroviral development those mothers in need of HAART can be reassured that HAART gives a survival benefit to the mother and reduces the transmission risk of HIV to her baby 7-fold,19 and this outweighs the risks for adverse pregnancy outcomes associated with HAART. However, it can be argued, based on the observed association of HAART with PTDs, SGA and stillbirths, that either zidovudine monotherapy plus PLCS (or single-dose nevirapine with 1 week of zidovudine plus lamivudine to cover the long nevirapine half-life) or delaying the initiation of HAART to the third trimester is preferred in mothers with high CD4 counts (>350 cells/mm3) and low HIV VL (<10 000 RNA copies/mL). This is particularly important in resource-poor settings where care for severely pre-term babies may be limited.
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Funding |
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TopAbstractIntroductionTeratogenicityMitochondrial toxicityAdverse outcomes of pregnancy...Concluding commentsFundingTransparency declarationsReferences |
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No funding was received to support the preparation of this article.
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Transparency declarations |
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TopAbstractIntroductionTeratogenicityMitochondrial toxicityAdverse outcomes of pregnancy...Concluding commentsFundingTransparency declarationsReferences |
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G. P. T. has received unconditional education support from the pharmaceutical industry to attend conferences as well as honoraria to present at postgraduate education meetings. G. P. T. is the principal investigator of research projects on the management of HIV infection during pregnancy funded by pharmaceutical companies through Imperial College, London. F. M. has received unconditional education support from the pharmaceutical industry to attend medical conferences.
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References |
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TopAbstractIntroductionTeratogenicityMitochondrial toxicityAdverse outcomes of pregnancy...Concluding commentsFundingTransparency declarationsReferences |
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4
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21
Schulte J, Dominguez K, Sukalac T, et al. Declines in low birth weight and preterm birth among infants who were born to HIV-infected women during an era of increased use of maternal antiretroviral drugs: pediatric spectrum of HIV disease, 1989–2004. Pediatrics (2007) 119:e900–6.
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33
Lallemant M, Jourdain G, Le Coeur S, et al. Single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of HIV-1 in Thailand. N Engl J Med (2004) 351:217–28.
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