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HAART Can Eliminate HIV Mother-To-Child Transmission (MTCT). Properly Timed Effective Use of HAART Can Prevent MTCT
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Low rates of mother-to-child transmission of HIV following effective pregnancy interventions in the United Kingdom and Ireland, 2000-2006
AIDS:Volume 22(8)11 May 2008p 973-981
Townsend, Claire La; Cortina-Borja, Marioa; Peckham, Catherine Sa; de Ruiter, Annemiekb; Lyall, Hermionec; Tookey, Pat Aa
From the aMRC Centre of Epidemiology for Child Health, UCL Institute of Child Health, University College London, London, UK
bGuys & St Thomas' NHS Foundation Trust, London, UK
cImperial College Healthcare NHS Trust, London, UK.
"Our findings suggest that offering HIV-infected women choices about HIV treatment and mode of delivery, according to current guidelines, has led to very low rates of MTCT..... The overall mother-to-child transmission rate was 1.2% and 0.8% (40/4864) for women who received at least 14 days of antiretroviral therapy. .... Among 2117 infants born to women on highly active antiretroviral therapy (HAART) with viral load less than 50 copies/ml, only three (0.1%) were infected, two with evidence of in-utero transmission..... There was evidence that being on HAART at conception and starting HAART earlier in pregnancy were associated with a lower risk of transmission after adjusting for viral load; this could be due to an increased risk of in-utero transmission before initiation of treatment. In these analyses we used viral loads closest to delivery, which might not reflect the infant's exposure to high maternal viral load at earlier stages of pregnancy. Of the nine infected children born to women with low or undetectable viral load, four had detectable virus at birth and were probably infected during fetal life. With postpartum transmission in developed countries now rare and intra-partum transmission highly preventable, in-utero transmission is likely to account for an increasing proportion of perinatal infections. The benefits of early treatment, however, must be weighed against concerns about drug toxicities and adverse pregnancy outcomes [26-28]; we have previously reported an increased risk of premature delivery associated with HAART in this population [29]."
Abstract
Aim: In the United Kingdom (UK) and Ireland, avoidance of breastfeeding and alternative combinations of antiretroviral therapy regimen and mode of delivery are recommended according to maternal clinical status. The aim of this analysis was to explore the impact of different strategies to prevent mother-to-child transmission at a population level.
Design: Comprehensive national surveillance study.
Methods: Pregnancies in diagnosed HIV-infected women in the UK and Ireland are notified to the National Study of HIV in Pregnancy and Childhood; infant infection status is subsequently reported. Factors associated with transmission in this observational study were explored for singleton births between 2000 and 2006.
Results:
The overall mother-to-child transmission rate was 1.2% (61/5151, 95% confidence interval: 0.9-1.5%), and 0.8% (40/4864) for women who received at least 14 days of antiretroviral therapy.
Transmission rates following combinations recommended in British guidelines were 0.7% (17/2286) for highly active antiretroviral therapy with planned Caesarean section, 0.7% (4/559) for highly active antiretroviral therapy with planned vaginal delivery, and 0% (0/464) for zidovudine monotherapy with planned Caesarean section (P = 0.150).
Longer duration of highly active antiretroviral therapy was associated with reduced transmission after adjusting for viral load, mode of delivery and sex (adjusted odds ratio = 0.90 per week of highly active antiretroviral therapy, P = 0.007). Among 2117 infants born to women on highly active antiretroviral therapy with viral load less than 50 copies/ml, only three (0.1%) were infected, two with evidence of in-utero transmission.
Conclusion: Sustained low HIV transmission rates following different combinations of interventions in this large unselected population are encouraging. Current options for treatment and delivery offered to pregnant women according to British guidelines appear to be effective.
Introduction
Mother-to-child transmission (MTCT) rates for diagnosed HIV-infected women in the UK and Ireland fell from about 20 to 2% between 1993 and 1998 [1]; transmission rates of 1-2% have been reported in studies from resource-rich countries in recent years, owing to effective antiretroviral therapy (ART), appropriate management of delivery, and avoidance of breastfeeding [2-5].
Highly active antiretroviral therapy (HAART) is now the standard of care in most resource-rich countries. British HIV Association (BHIVA) guidelines also support zidovudine monotherapy and planned Caesarean section as an alternative to HAART for women with high CD4 cell counts and pretreatment viral load of less than 6000-10 000 copies/ml [6]. The benefits of elective Caesarean section in relation to MTCT were demonstrated in the mid-1990s, before HAART was widely used [7], but it is unclear whether planned Caesarean section delivery confers additional benefit for women who achieve viral suppression on HAART [8,9]. Few studies have addressed the impact of different combinations of interventions on MTCT at a population level.
Uptake of antenatal HIV testing rose rapidly following the introduction of routine screening policies in 1999 in Ireland [10] and between 2000 and 2003 in the UK [11], with the estimated proportion of infected women diagnosed before delivery increasing from about 70% in 2000 to about 95% since 2005 [12]. In the UK and Ireland, information on paediatric and obstetric HIV is collected through comprehensive, population-based surveillance. We explore MTCT rates, and factors associated with MTCT, for infants born to diagnosed HIV-infected women between 2000 and 2006.
Discussion
These results are based on observational data collected in the UK and Ireland. Routine antenatal HIV testing and professional guidelines [6] were available throughout this period, outlining a range of strategies for the management of HIV in pregnancy. Although these guidelines recommend that most women should receive HAART in pregnancy, zidovudine monotherapy with planned Caesarean section remains an alternative for asymptomatic women with high CD4 cell count and low viral load. A more tolerant approach to mode of delivery for women who achieve full viral suppression on HAART has become evident, with rates of planned vaginal delivery rising [16].
MTCT rates remained very low: 1.2% overall (slightly lower in recent years) and 0.8% for women on treatment for at least the last 2 weeks of pregnancy. These low rates are consistent with reports from elsewhere in Europe and the United States [3,5]. We observed similar transmission rates among women on HAART who had elective Caesarean sections or planned vaginal deliveries (0.7% in both groups), and the transmission rate was particularly low (0.1%) in the 2100 women on HAART who achieved viral suppression. In cases where transmission occurred despite HAART and planned vaginal or elective Caesarean section delivery, most infections could be explained by failure to reduce viral load, mainly because of short duration of treatment or adherence problems, or to in-utero transmission. An audit undertaken to investigate circumstances surrounding cases of perinatal HIV transmission in England reported similar findings [17].
In this population, zidovudine monotherapy is likely to have been used selectively according to the BHIVA guidelines [6], a strategy associated with low rates of drug resistance [18,19]. Our findings suggest that selective zidovudine monotherapy combined with elective Caesarean section is a reasonable approach for preventing MTCT (no infections reported in over 450 infants).
Lack of ART and vaginal delivery, particularly unplanned, remained significantly associated with transmission after controlling for viral load near delivery. Before the widespread use of HAART, prematurity was identified as a risk factor for transmission [20]. In this analysis, the increased risk of transmission associated with very premature delivery was not observed in women on HAART. An increased risk of MTCT for girls has been previously reported, both for HIV and for hepatitis C virus [21-23], but in this study, the increased rate for girls was no longer significant when the analysis was restricted to cases where maternal viral load was recorded, possibly owing to reduced numbers.
Among women on HAART, we found no difference in transmission rates by type of regimen, even though differences in response to protease inhibitor and NNRTI-based regimens in pregnant women have been reported [24]. Any effect, however, might have been attenuated in recent years by the restriction of nevirapine to women with CD4 cell counts below 250 cells/_l [6,25], who may also have higher baseline viral loads.
There was evidence that being on HAART at conception and starting HAART earlier in pregnancy were associated with a lower risk of transmission after adjusting for viral load; this could be due to an increased risk of in-utero transmission before initiation of treatment. In these analyses we used viral loads closest to delivery, which might not reflect the infant's exposure to high maternal viral load at earlier stages of pregnancy. Of the nine infected children born to women with low or undetectable viral load, four had detectable virus at birth and were probably infected during fetal life. With postpartum transmission in developed countries now rare and intra-partum transmission highly preventable, in-utero transmission is likely to account for an increasing proportion of perinatal infections. The benefits of early treatment, however, must be weighed against concerns about drug toxicities and adverse pregnancy outcomes [26-28]; we have previously reported an increased risk of premature delivery associated with HAART in this population [29].
This national surveillance study is designed to include all pregnant women diagnosed with HIV any time up to delivery, regardless of maternal characteristics or uptake of interventions. Alignment of NSHPC reports with unlinked anonymous neonatal seroprevalence data suggests that about 95% of HIV-infected women are diagnosed before delivery [12]. Given the active nature of the complementary obstetric and paediatric reporting systems, and the high estimated overall detection rates, very few cases of diagnosed HIV infection in pregnancy are likely to remain unreported.
Children whose infection status had not yet been reported were more likely than those with known infection status to have recognized risk factors for transmission. We have, however, shown that although this bias could potentially lead to an underestimate of the overall transmission rate any effect is likely to be small. Owing to the observational nature of these data they should be interpreted in the context of current guidelines, in which interventions are recommended on the basis of timing of maternal diagnosis, clinical presentation, response to treatment, personal circumstances and choice. Since a randomized trial would be inappropriate, these population data provide important evidence to support the targeted use of different combinations of interventions for preventing MTCT.
The low rate (1.2%) of MTCT of HIV among diagnosed pregnant women in the UK and Ireland is a remarkable achievement. Continuing to improve the offer and uptake of antenatal HIV testing could have a significant impact on further reducing MTCT, since most perinatally acquired infection is now in infants whose mothers are among the approximately 5% of infected women who remain undiagnosed at delivery [12,17]. Ensuring that women are diagnosed in time to take up appropriate interventions remains a priority, and early testing for all pregnant women should continue to be promoted. Our findings suggest that offering HIV-infected women choices about HIV treatment and mode of delivery, according to current guidelines, has led to very low rates of MTCT.
Methods
Surveillance of obstetric and paediatric HIV in the UK and Ireland is carried out through the National Study of HIV in Pregnancy and Childhood (NSHPC). Pregnancies in women with diagnosed HIV are notified through an active obstetric surveillance scheme, run under the auspices of the Royal College of Obstetricians and Gynaecologists. Children with HIV infection and infants born to infected women are notified through the British Paediatric Surveillance Unit [13], or directly to the NSHPC. This paper is based on singleton births between 2000 and 2006 (when routine antenatal HIV screening and HAART were widely available [12]) to women diagnosed with HIV infection before delivery and reported to the NSHPC by June 2007. Some women (n = 689) had two or more pregnancies during the study period. Multiple births were excluded (n = 98); none of the twins or triplets was infected (0/165).
Infection status of nonbreastfed infants was classified as 'presumed uninfected' if a PCR test result was negative after 1 month of age, and 'confirmed uninfected' following a subsequent negative PCR after 3 months of age, or a negative HIV antibody test after 18 months of age. Infants were classified as 'presumed infected' if one positive PCR was reported, and 'confirmed infected' if two positive PCR tests were reported, or a positive antibody test after 18 months of age. In these analyses, because preliminary results rarely conflict with later ones, 'presumed' and 'confirmed' results were grouped.
Maternal ART in pregnancy was categorized as none, monotherapy, dual therapy and HAART (three or more drugs); only antepartum treatment was considered in these analyses. HAART was categorized according to whether a protease inhibitor or nonnucleoside reverse transcriptase inhibitor (NNRTI) was included. Gestational age was in completed weeks, and for some analyses categorized as 32 or less, 32-34, 35-36 and at least 37 weeks gestation. Mode of delivery was classified as elective Caesarean section, emergency Caesarean section, and vaginal delivery (reported by obstetric respondents as planned or unplanned). Emergency Caesarean section included those carried out after rupture of membranes or onset of labour, or for other obstetric indications. Duration of rupture of membranes was not requested until 2007 and was not available for this analysis.
Maternal clinical status was classified as symptomatic if AIDS or HIV-related symptoms were reported in pregnancy [14]. Latest antepartum maternal CD4 cell count was used and categorized accordingly: less than 200, 200-349, 350-499 and at least 500 cells/_l. Maternal HIV plasma viral load closest to delivery and up to 7 days postpartum was used (pretreatment viral loads were not available). For some analyses, viral load was classified as less than 50 (undetectable), 50-999, 1000-9999 and at least 10 000 copies/ml; when viral load was used as a continuous variable, midpoints were taken for values below assay detection limits (68 viral loads were reported as 'less than 400 copies/ml'). For logistic regression analyses, viral load was log10 transformed.
Data were managed in an Access 2002 database (Microsoft Corp., Redmond, Washington, USA), compiled using R version 4.1.2 [15], and analysed using Stata version 9.0 (Stata Corp., College Station, Texas, USA). Categorical variables were compared using _2 tests or Fisher's exact tests, means using t-tests, and medians using Kruskal-Wallis tests. Logistic regression models were fitted to obtain odds ratios (ORs) and 95% confidence intervals (CIs). Likelihood ratio tests were used to compare nested logistic regression models.
Results
Maternal characteristics
There were 5930 singleton infants born between 2000 and 2006, increasing from 358 in 2000 to 1120 in 2006. Most mothers were black African, received antenatal HAART and delivered by elective Caesarean section (Table 1). About 45% (2691/5861) of women were diagnosed before pregnancy. Five women acquired HIV vertically from their own mothers. Among women on HAART, 24.1% (1075/4469) started it before pregnancy, and the median gestational age at initiation for those starting in pregnancy was 25.9 weeks [interquartile range (IQR): 22.4-28.9 weeks]. Median gestational age at initiation of monotherapy was 28.0 weeks (IQR: 25.4-30.0). Median viral load was less than 50 copies/ml (IQR: less than 50-184 copies/ml) following HAART and 355 copies/ml (IQR: 54-1977 copies/ml) following monotherapy.
Infants with unreported infection status
Infection status was not yet reported for 13.1% (779/5930) of infants at time of analysis [but for only 8.7% (419/4810) of infants born 2000-2005]. Reasons for unreported infection status were: paediatric notification not yet received (birth only reported through obstetric scheme; 54.0%, 421/779), paediatric follow-up pending (28.4%, 221/779), child lost to follow up (11.4%, 89/779), child left the UK/Ireland (3.5%, 27/779), and death (mostly associated with prematurity or congenital abnormality) (2.7%, 21/779).
Children with unreported infection status did not differ significantly from those with known infection status in terms of maternal HIV exposure group, clinical status or mode of delivery, but more were born at less than 32 weeks gestation (5.0%, 38/758, versus 2.3%, 115/5002, P < 0.001), to untreated women (5.9%, 43/733, versus 2.8%, 143/5027, P < 0.001), and to women with viral load of at least 1000 copies/ml (21.8%, 130/596, versus 18.7%, 764/4096, P = 0.061), factors associated with each other.
Overall mother-to-child transmission rates
The overall transmission rate was 1.2% (61/5151, 95% CI: 0.9-1.5%), and lower in 2003-2006 (1.0%, 38/3695) than in 2000-2002 (1.6%, 23/1456) (P = 0.069). Transmission from women on ART for at least the last 14 days of pregnancy was 0.8% (40/4864, 95% CI: 0.6-1.1%), regardless of type of therapy or mode of delivery. Transmission was not associated with maternal ethnic group, birth region, or HIV exposure group (data not shown), or maternal symptoms or low CD4 cell count (Table 2). Univariable risk factors for transmission included no maternal ART, vaginal delivery (particularly if unplanned), prematurity (less than 32 weeks gestation), female sex and detectable viral load (Table 2). Table 3 shows all infants (and proportion infected) by maternal ART and mode of delivery.
In the multivariable analysis (n = 4892; Table 4) including ART, mode of delivery, gestational age and sex (but not viral load), being untreated (adjusted odd ratio (AOR) = 9.08, P < 0.001) was the strongest risk factor for transmission, and girls were more likely to be infected than boys (AOR = 1.91, P = 0.023). Prematurity (less than 32 weeks) was a significant risk factor for transmission (AOR = 3.55, P = 0.010); however, of the seven women who had infected infants born at less than 32 weeks gestation, all were either untreated (n = 3) or treated for less than 3 weeks (range: 1-19 days), and all but one delivered vaginally. Prematurity was not a significant risk factor for transmission among women on HAART (AOR = 1.32, 95% CI: 0.30-5.82, P = 0.714).
In the multivariable model, vaginal delivery was associated with a nonsignificant 1.8-fold increased risk of transmission compared with elective Caesarean section (AOR = 1.82, P = 0.076). Information on whether vaginal deliveries were planned or unplanned was available for 69.1% (775/1122). After adjusting for ART, gestational age and sex, unplanned vaginal delivery was associated with a significantly increased risk of transmission (AOR = 4.16, 95% CI: 1.66-10.41, P = 0.002) compared with elective Caesarean section, but planned vaginal delivery was not (AOR = 1.56, 95% CI: 0.65-3.72, P = 0.319).
The association between mode of delivery and transmission varied by type of therapy, but owing to small numbers could not be explored adequately using interaction terms; analyses stratified by therapy are presented later.
Viral load was reported for 79.5% (4096/5151) of women, but for significantly fewer untreated than treated women (49.7%, 71/143, versus 82.3%, 4021/4884, P < 0.001), and infected than uninfected infants (67.2%, 41/61, versus 79.7%, 4055/5090, P = 0.024). The closest viral load to delivery was a median 23 days before delivery (IQR: 10-44 days). In the multivariable analysis (n = 4084) controlling for ART, mode of delivery, gestational age and sex, each log10 increase in viral load was associated with a 2.4-fold increased risk of transmission (AOR = 2.41, P < 0.001) (Table 4). In this model, lack of ART (AOR = 3.17, P = 0.023) and vaginal delivery (AOR = 2.40, P = 0.033) were strongly associated with transmission, but gestational age and sex were not.
Although HIV-infected women in the UK and Ireland are recommended to formula feed, breastfeeding was reported in 0.6% (29/4399) of infants with information provided; three were infected, all born to untreated women (two declined ART, one was diagnosed close to delivery).
Transmission following highly active antiretroviral therapy
MTCT rate for women on HAART was 1.0% (40/4120) (Table 2) and was not significantly different when HAART included an NNRTI (0.9%, 18/1959), a protease inhibitor (1.1%, 20/1795, P = 0.625), both an NNRTI and a protease inhibitor (0.8%, 2/258), or neither (0%, 0/108, P = 0.847). Comparing protease inhibitor with NNRTI regimens, there was no difference in MTCT rates after adjusting for mode of delivery, sex and viral load (AOR = 1.31, 95% CI: 0.62-2.76, P = 0.482) (as previously noted, gestational age was not a significant risk factor for transmission in women on HAART and was therefore excluded from these analyses). HAART at conception was associated with a lower risk of transmission than HAART started in pregnancy (0.1%, 1/928, versus 1.3%, 39/2967, P = 0.001), but this was only of borderline significance after adjusting for mode of delivery, sex and viral load (AOR = 0.18, 95% CI: 0.02-1.33, P = 0.093). Among women who started HAART during pregnancy, those who transmitted (n = 34) started later than those who did not (median gestational age at initiation: 30.1 weeks, IQR: 27.4-32.6 weeks, versus 25.9 weeks, IQR: 22.4-28.7 weeks, P < 0.001). Each additional week of treatment corresponded to a 10% (AOR = 0.90, 95% CI: 0.84-0.97, P = 0.007) reduction in the risk of transmission after adjusting for viral load (closest to delivery), mode of delivery and sex.
Among women on HAART, there was no statistically significant difference in MTCT rates between elective Caesarean section (0.7%, 17/2286) and planned vaginal delivery (0.7%, 4/559; AOR = 1.24, 95% CI: 0.34-4.52, P = 0.746, adjusted for sex and viral load); viral load was undetectable in 58.7% (1135/1934) of those having elective Caesarean sections, and 79.0% (417/528) having planned vaginal deliveries (P < 0.001). Only three transmissions were reported among 2117 infants born to women on HAART with undetectable viral load (0.1%, 95% CI: 0.0-0.4%); two were born by elective Caesarean section (0.2%, 2/1135) and one by planned vaginal delivery (0.2%, 1/417). Two of the three infants (one born vaginally) had positive PCR results within 72 h of birth, suggesting possible in-utero transmission. MTCT rates were higher in women on HAART who had emergency Caesarean sections (1.7%, 15/877) or unplanned vaginal deliveries (3.3%, 4/122) compared with elective Caesarean sections (P = 0.027 and P = 0.019, respectively).
Eighteen other women had infected infants despite HAART and either planned vaginal delivery or elective Caesarean section. For 10 of them, one or more of the following applied: short duration of treatment, high viral load near delivery (range: 8500-285 000), adherence problems. There were six transmissions from women with low but detectable viral load (≥50 and <1000 copies/ml); two had planned vaginal deliveries (2.5%, 2/81) and four elective Caesarean sections (0.8%, 4/471, P = 0.215). Two of these six infected infants had positive PCR results within 72 h of birth (both born by elective Caesarean section). The remaining two women received HAART for at least 1 month, but no viral loads were reported.
Information on neonatal prophylaxis was provided for 20 of the 21 infants infected despite maternal HAART and planned vaginal or elective Caesarean section delivery, and all were treated; 18 had breastfeeding status reported, and none was breastfed.
Transmission following zidovudine monotherapy
The mothers of 638 infants received prophylactic zidovudine monotherapy in pregnancy, and three infants were infected (0.5%, 95% CI: 0.1-1.4%); all three women were treated for less than 1 month, had detectable viral load (range: 474-3000 copies/ml) and delivered vaginally. The transmission rate following monotherapy and elective Caesarean section was 0% (0/464, 95% CI: 0-0.8%), with median viral load of 400 copies/ml (IQR: 61-1992 copies/ml); this transmission rate was not significantly different from that following HAART and planned vaginal delivery (0.7%) or elective Caesarean section (0.7%, P = 0.150). The transmission rate following monotherapy and emergency Caesarean section was 0% (0/116, 95% CI: 0-3.4%), with median viral load of 597 copies/ml (IQR: 84-3195 copies/ml).
Adjustment for unreported infection status
Potential bias introduced by excluding infants with unreported infection status was investigated by computing likely infection status based on maternal treatment and viral load categories. A crude transmission rate of 9.1% was assumed for all untreated women (Table 2) and those with missing treatment information (viral load was unavailable for over 70% of these women). Among treated women, actual transmission rates by viral load levels were 0.1% (3/2299) for viral load of less than 50 copies/ml, 1.2% (12/1003) for 50-999 copies/ml, 1.4% (6/414) for 1000-9999 copies/ml, 4.6% (14/305) for at least 10 000 copies/ml and 1.0% (9/863) for those where viral load was not recorded. Using these transmission rates to compute likely infection status, an estimated 1.8% (14/779) of children with unreported infection status would be infected, which would increase the overall transmission rate marginally to 1.3% (75/5930, 95% CI: 1.0-1.6%).
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