Earlier initiation of ART and further decline in mother-to-child HIV transmission rates, 2000–2011 : AIDS

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Epidemiology and Social

Earlier initiation of ART and further decline in mother-to-child HIV transmission rates, 2000–2011

Townsend, Claire L.a; Byrne, Lauraa; Cortina-Borja, Marioa; Thorne, Clairea; de Ruiter, Annemiekb; Lyall, Hermionec; Taylor, Graham P.c; Peckham, Catherine S.a; Tookey, Pat A.a

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AIDS 28(7):p 1049-1057, April 24, 2014. | DOI: 10.1097/QAD.0000000000000212
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An estimated 96 000 people were living with HIV in the UK in 2011, with about 25% of heterosexual HIV-positive women remaining undiagnosed [1]. The overall prevalence of HIV among pregnant women in England was 2.2 per 1000, and 23 per 1000 in sub-Saharan African-born women [1]. Rates of mother-to-child transmission (MTCT) of HIV in untreated resource-rich nonbreastfeeding populations range from 13 to 32% [2]. However, perinatal HIV transmission is almost entirely preventable through a multipronged approach involving universal antenatal HIV screening, careful management of pregnancy including appropriate antiretroviral therapy (ART) and mode of delivery, neonatal antiretroviral prophylaxis, and avoidance of breastfeeding. These interventions have resulted in dramatic reductions in MTCT, and many countries in northern and western Europe have already achieved rates of less than 2% [3–6], in line with the WHO goal for virtual elimination of MTCT in the European region by 2015 [7]. Rates in eastern European countries remain higher, although there has also been significant progress [8,9]. In the UK, success in preventing MTCT has resulted from high uptake of antenatal HIV screening (around 97%) [1,10], effective national guidelines [11], and a coordinated multidisciplinary approach to the management of HIV-positive pregnant women, involving obstetric, HIV, and pediatric services within the National Health Service.

In the context of low MTCT rates in resource-rich settings, questions around optimal management remain, and guidelines have diverged both within and between countries [12,13]. For example, the optimal timing of initiation of combination antiretroviral therapy (cART) in pregnancy is unclear [13,14], and requires consideration of the benefits and potential risks of longer treatment exposure during pregnancy [11,14]. Whether elective cesarean section confers a protective effect in women with low but detectable HIV viral load is also unclear and evidence is sparse, resulting in diverging cesarean section rates across Europe [15]. Currently, the British HIV Association recommends vaginal delivery only for women with suppressed viral load (<50 copies/ml), with consideration of planned cesarean section if viral load is 50–400 copies/ml [11]; the threshold for vaginal delivery ranges from less than 50 copies/ml to less than 1000 copies/ml in other countries [13,16], and is less than 400 copies/ml in the UK National Institute for Health and Care Excellence obstetric guidelines [17].

We previously reported an MTCT rate of 1% in the UK and Ireland in 2003–2006, lower than in the previous 3 years (1.6%) [4]. Since then, clinical practice has continued to evolve, with national pregnancy management guidelines updated in 2008 and 2012 [11,18] and recommendations for improving care pathways issued following an audit of perinatal transmissions [19]. The population of pregnant women with HIV in the UK has also changed, with increases in incidence of pregnancy among HIV-positive women [20] and in numbers of repeat pregnancies and conceptions on cART among diagnosed women [21,22]. In this article, we describe trends in the characteristics of HIV-positive pregnant women in the UK and Ireland and MTCT in particular groups wherein evidence is currently lacking (e.g. women with low, detectable viral load), and explore whether MTCT rates have continued to decline following changes in policy and practice.


In the UK and Ireland, data on pregnant HIV-positive women and their children are collected from all maternity units through a comprehensive population-based surveillance study, the National Study of HIV in Pregnancy and Childhood (NSHPC) [4,23]. Pregnancies in women delivering in 2000–2011, diagnosed with HIV before delivery, and reported by March 2013 were included in these analyses. To highlight differences in maternal and pregnancy characteristics over this period, pregnancies delivered in 2007–2011 were compared with those in 2000–2006 [4]. Analyses included singleton births only, with twins described separately.

Infection status was classified as ‘presumed uninfected’ based on a negative PCR test after 1 month of age, and ‘confirmed uninfected’ following a subsequent negative PCR after 3 months or a negative HIV antibody test after 18 months (in the absence of conflicting positive PCR results). Infants were classified as ‘presumed infected’ based on a single positive PCR, and ‘confirmed infected’ if two positive PCR tests were reported, or a positive antibody test after 18 months of age. ‘Presumed’ and ‘confirmed’ results were combined in these analyses. Classification of timing of transmission (in utero, intrapartum, etc.) is shown in Table 1. As breastfeeding was uncommon in this population, those reported to have been breastfed and those with clear evidence of postnatal transmission (negative PCR ≥6 weeks after birth, and subsequent positive test) were excluded from the main analyses.

Table 1:
Timing of HIV transmission in infants.

ART during pregnancy prior to delivery was categorized as none, zidovudine alone, two antiretroviral drugs, or cART (three or more drugs). Gestational age was in completed weeks and less than 37 weeks was considered preterm. Mode of delivery was classified as elective cesarean section (prelabor, prerupture of membranes), emergency cesarean section (after rupture of membranes and/or onset of labor, or for other obstetric indications, e.g. preeclampsia), or vaginal delivery (reported by respondents as planned or unplanned). Date of first attendance for antenatal care was collected from mid-2008.

Maternal CD4+ cell count closest to delivery was classified as less than 200, 200–349, 350–499, and at least 500 cells/μl. HIV plasma viral load closest to delivery (during pregnancy or up to 7 days postpartum) was selected; where treatment commenced more than a month before delivery, viral loads measured less than 7 days after treatment initiation were not included. Viral load was categorized as less than 50 (undetectable), 50–399, 400–999, 1000–9999, and at least 10 000 copies/ml, and those reported at specific assay detection limits (<80, <100, <200, <300 or <400 copies/ml) were included in the ‘50–399 copies/ml’ group (n = 285). Baseline viral load, used in the analysis of cART duration and MTCT, was the earliest viral load measured during pregnancy or up to 2 weeks before conception, prior to or up to 1 week after cART initiation, and was categorized as less than 30 000, 30 000–99 999, and at least 100 000 copies/ml, in line with UK recommendations for timing of cART initiation among women not requiring treatment for their own health [11].

Data were managed in Access 2010 (Microsoft Corp., Redmond, Washington, USA), compiled using R version 2.14.2 [24], and analyzed using Stata version 12.1 (Stata Corp. LP, College Station, Texas, USA). Categorical variables were compared using χ2 tests or Fisher's exact tests, and medians using Kruskal–Wallis tests. We fitted generalized additive models (GAMs) using R version 2.14.2 [24] with a logistic link and cubic spline term for cART duration to estimate continuous changes in MTCT probability, and similar GAMs adjusting for baseline viral load category.


Baseline characteristics

Baseline characteristics for the 12 486 singleton pregnancies delivered between 2000 and 2011 are shown in Table 2; almost half (6020/12 486) were in women with more than one reported pregnancy during this period. The proportion of women diagnosed with HIV prior to conception (in previous pregnancies and other settings) increased over time (P <0.001, comparing 2000–2006 with 2007–2011), as did the proportion on cART at any time in pregnancy (P <0.001), and delivering vaginally (P <0.001) (Table 2). There were declines in the proportions of women who acquired HIV through injecting drug use (P <0.001), remained untreated in pregnancy (P <0.001), and delivered preterm (P <0.01). Among 3167 pregnancies with date of first attendance for antenatal care reported (2009–2011), this was during the third trimester (27 weeks gestation or more) for 5.1% (160/3167) with no significant trend over time (P = 0.28).

Table 2:
Maternal demographic, treatment, and pregnancy characteristics by time period.

cART was more likely to have been initiated prior to conception in the later period (Table 2, P <0.001). Among those starting during pregnancy, cART was initiated earlier: median gestation at initiation declined from 27.4 weeks [interquartile range (IQR) 22.6–30.6] in 2000–2001 to 21.3 weeks (IQR 18.3–24.4) in 2010–2011 (trend by year, P <0.001). cART was initiated later in women diagnosed during pregnancy compared with those diagnosed before who were not on cART at conception (25.0 versus 22.9 weeks, P <0.001), but similar trends were observed in both groups.

Among women with baseline viral load available (n = 6217, 2000–2011), cART was started significantly earlier in women with higher baseline viral load (median 22.1 weeks gestation, IQR 18.3–26.4, for viral load ≥100 000 copies/ml, versus 24.4 weeks, IQR 21.4–27.7, for viral load <30 000 copies/ml, P <0.001). Viral load closest to delivery was available in significantly more pregnancies in 2007–2011 (85.9%, 5512/6415) than 2000–2006 (73.7%, 4475/6071, P <0.001). Despite an increase in the proportion of women with undetectable viral load (<50 copies/ml) nearest to delivery (Table 2, P <0.001), 20.5% of women in 2007–2011 did not achieve virological suppression by delivery (median 180 copies/ml, IQR 81–659, measured a median 14 days before delivery, IQR 8–33).

Trends in mother-to-child HIV transmission over time

The MTCT rate declined from 2.1% [17/816, 95% confidence interval (CI): 1.2–3.3%] in 2000–2001 to 1.4% (21/1555) in 2002–2003, 1.1% (24/2148) in 2004–2005, 0.72% (18/2500) in 2006–2007, 0.60% (15/2521) in 2008–2009, and 0.46% (nine of 1975, 95% CI: 0.21–0.86%) in 2010–2011 (trend by year, P = 0.01). The transmission rate was significantly lower in 2007–2011 (0.57%, 33/5788, 95% CI: 0.39–0.80%) than in 2000–2006 (1.2%, 71/5727; P <0.001). Infection status was reported for 94.3% of children born in 2000–2006 (5727/6071), and a slightly lower proportion of those born in 2007–2011 (90.2%, 5788/6415), because of reporting delay in recent years. In 2007–2011, there were no significant differences between children with known infection status and those with unreported infection status in terms of maternal characteristics, including type of treatment (P = 0.49), timing of cART initiation (P = 0.29), cART duration in pregnancy (Kruskal–Wallis test, P = 0.30), or viral load nearest to delivery (P = 0.44) (data not shown, categories as in Table 3). Differences in baseline characteristics according to whether infection status was reported were previously described for children born 2000–2006 [4].

Table 3:
Mother-to-child transmission rates in 2007–2011 by treatment and, for women on combination antiretroviral therapy, by mode of delivery and viral load.

Although this was a largely nonbreastfeeding population, 53 infants were known to have been breastfed (42 with infection status reported, five infected), and an additional 10 infants had laboratory evidence of postnatal acquisition according to our definition (Table 1), despite no report of breastfeeding. These 63 infants were excluded from subsequent analyses.

Mother-to-child HIV transmission in 2007–2011

MTCT rates for infants born 2007–2011 are shown in Table 3. The transmission rate among women on cART with undetectable viral load near delivery was 0.05% (two of 3859, 95% CI: 0.01–0.19%; both transmissions likely intrapartum according to our definition, Table 1). The MTCT rate was 0.19% (four of 2105) in women on cART at conception, among whom delivery viral load was undetectable in 93% (1894/2045), 50–399 copies/ml in 5% (101/2045), and at least 400 copies/ml in 2% (50/2045); delivery viral load was detectable (n = 3) or missing (n = 1) in all those who transmitted. There was no statistically significant difference in MTCT rates between women on nonnucleoside reverse transcriptase inhibitor-based and protease inhibitor-based cART (Table 3, P = 0.09), but there were clear differences in timing of cART initiation, with nonnucleoside reverse transcriptase inhibitor-based cART more likely to be initiated preconception than protease inhibitor-based cART (78.6%, 1022/1301 versus 27.2%, 1116/4103, P <0.001).

Although 16 of 54 untreated women (30%; Table 3) were reported to have declined antenatal treatment, many accessed other interventions: 28% (15/53) delivered by elective cesarean section, half (25/49) received intrapartum ART, and 47 infants received antiretroviral prophylaxis (18 a single drug, 29 two or more, information missing for seven). Five of 32 untreated women had undetectable viral loads reported (range 2 days to 18 weeks before delivery), and none transmitted; scrutiny of reports suggested that these five were likely elite controllers. Four of the 54 infants born to untreated mothers were infected, all in utero.

Overall, there were 25 transmissions in 2007–2011 among women on cART in pregnancy, of whom four were on cART at conception. In those starting cART in pregnancy and with information available (18/21), median duration of cART was 12.9 weeks (IQR 4.3–19). Median maternal viral load was 712 copies/ml (IQR 194–19 214 copies/ml, n = 20) at a median 13.5 days before delivery (IQR 0.5–23.5). Four infected infants were born preterm by emergency cesarean section (n = 3) or unplanned vaginal delivery (n = 1), including two at less than 32 weeks.

Mother-to-child HIV transmission, mode of delivery, and viral load, 2000–2011

To explore the association between low viral load and MTCT, data on all infants born 2000–2011 to women on cART with viral load less than 1000 copies/ml were analyzed. The overall transmission rate in women with undetectable viral load (<50 copies/ml) was 0.09% (Table 4), and 0.06% (four of 6345) excluding two in-utero transmissions; there was no significant difference between elective cesarean section and planned vaginal delivery (0.11 versus 0.15%, P = 0.53). For all modes of delivery, risk of transmission was significantly higher when viral load was 50–399 copies/ml than when fully suppressed (<50 copies/ml) (Table 4). Among women with viral load 50–399 copies/ml, MTCT rates were 0.77% following elective cesarean section and 1.6% following planned vaginal delivery (P = 0.39; Table 4). Women delivering by elective cesarean section had slightly shorter duration of cART than those who had planned vaginal deliveries in this group (median 12.4 versus 13.9 weeks, P = 0.007). Excluding five in-utero transmissions, the MTCT rate among women with viral load 50–399 copies/ml was 0.26% (two of 777) following elective cesarean section and 1.1% (two of 188) following planned vaginal delivery (P = 0.17). Excluding women with viral loads at, or presumed to be at, specific assay detection limits, the MTCT rate was 0.47% (three of 637) for elective cesarean section and 1.2% (two of 162) for planned vaginal delivery (P = 0.27), and results were similar when including all vaginal deliveries (planned, unplanned, and unclassified; Table 4). Few women with viral load of 400–999 copies/ml delivered vaginally, as this is not currently recommended in the UK.

Table 4:
Mother-to-child transmission rates by viral load and mode of delivery among women on combination antiretroviral therapy and delivering in 2000–2011.

Duration of combination antiretroviral therapy, 2000–2011

Median duration of cART among women delivering at term was 14.9 weeks (IQR 11.1–18.1), but only 10.1 weeks (IQR 6.1–14.1) in the 11.8% (764/6499) of women who delivered preterm. The influence of duration of cART in pregnancy on risk of MTCT was modeled among women who started cART in pregnancy or were untreated and delivered in 2000–2011 (n = 6206). MTCT probability declined rapidly initially as duration of cART increased (Fig. 1a), but varied substantially by baseline viral load group (Fig. 1b, n = 4327 with baseline viral load available). There was no evidence of interaction between baseline viral load groups and cART duration.

Fig. 1:
Probability of mother-to-child HIV transmission by duration of combination antiretroviral therapy.(a) Overall (n = 6206). (b) Stratified by baseline viral load among women with pretreatment viral load available (n = 3999). Note that Y-axis scales are different. (a) Gray shaded area = 95% prediction confidence intervals; dotted lines are shown at 0.5 and 1% probability of transmission. cART, combination antiretroviral therapy; MTCT, mother-to-child transmission; VL, viral load.

Updated transmission rates, 2000–2006

Including children born 2000–2006 whose infection status was reported since our previous published estimate of MTCT (1.2%, 61/5151) [4], the revised MTCT rate for this period was similar (1.2%, 71/5727) [4]. We previously reported zero transmissions among 464 women on zidovudine alone delivering by elective cesarean section; the updated data include one transmission in this group (one of 483, 0.21%, 2000–2006; one of 559, 0.18%, 2000–2011).


Altogether 495 live born twins or triplets were reported (2000–2011), comprising 243 twin pairs, two sets of triplets, and three infants whose twin was stillborn. MTCT occurred in only one multiple pregnancy (0.45%, one of 224), and the rate was not significantly different from that among singletons (P = 0.47). The overall transmission rate including twin births was 0.89% (105/11 740), compared with 0.90% (104/11 516) among singletons only.


The MTCT rate in over 5500 pregnancies in diagnosed HIV-positive women delivering in 2007–2011 in the UK and Ireland was 0.57% overall and 0.46% in 2010–2011, a four-fold decline from 2000–2001. Other key trends over this period included an increase in vaginal deliveries, a decline in the proportion of women receiving no antenatal ART to 1%, longer duration of cART in pregnancy (with more women conceiving on cART and earlier initiation among those starting in pregnancy), and an increase in the proportion of women delivering with viral load less than 50 copies/ml. Among the few women who received no antenatal ART, most took up other interventions and the MTCT rate in this group was 7.4%, similar to rates reported elsewhere [25].

Building on our previous findings showing that, adjusting for viral load and mode of delivery, longer duration of ART was significantly associated with reduced transmission risk [4], we now demonstrate an initially rapid decline in MTCT with each additional week of cART among women starting treatment in pregnancy, with continued decline up to about 15 weeks of cART. The predicted probability of MTCT was greater in higher viral load groups for any duration of cART, supporting current British guidelines that recommend that women with higher baseline viral loads should commence cART earlier in pregnancy than those with lower viral loads [11]. Decisions about when to initiate treatment in pregnancy also require consideration of factors such as immunological status and the potential for preterm delivery, which can lead to substantially shortened duration of cART. Preterm delivery occurred in 12% of women in our study, which is higher than in the general population (6.2% overall and 7.0% in black African women in England in 2005) [26], but substantially lower than in other HIV-positive populations, in whom rates of 18–20% have recently been reported [27,28].

Among women with fully suppressed viral load near delivery (<50 copies/ml), the MTCT rate was under 1 per 1000, significantly lower than the 1% transmission rate in over 1300 women with viral load 50–399 copies/ml. Among the latter, the MTCT rate after excluding in-utero transmissions was 1.1% following planned vaginal delivery and 0.26% following elective cesarean section, a difference that was not statistically significant (P = 0.17). Currently, British guidelines suggest a cautious approach for women with viral load 50–400 copies/ml, with consideration of elective cesarean section based on individual factors such as viral load trajectory, duration of and adherence to treatment, and obstetric factors [11]. Evidence to support the recommendation of vaginal delivery in women with low detectable viral load remains limited, and a cautious approach, therefore, seems appropriate.

A strength of this comprehensive surveillance study is that in the context of free antenatal care, high uptake of antenatal HIV testing [1], and study response rates of 90–95% [29], most HIV-positive pregnant women in the UK and Ireland are diagnosed before delivery and included in our study. Prevention of MTCT (PMTCT) has been one of the success stories of HIV prevention, and results from the NSHPC have demonstrated this at a population level over more than two decades, with a dramatic decline in MTCT among women diagnosed by delivery from around 20% in the early 1990s [30] to 2% by 2000–2001 [4], and 5 per 1000 in 2010–2011. MTCT rates of 0.5–1% have been reported from observational cohort studies in other resource-rich settings in Europe and North America [6,31–35]. However, to our knowledge, such low rates have not been previously achieved in such a large unselected population. In comparison, among over 7500 infants born to HIV-positive mothers in the United States in 2005–2008, the reported MTCT rate was 1.6% wherein maternal diagnosis occurred before labor and delivery [36].

Limitations of our study included missing delivery viral load data for 20% of women, a proportion similar to other studies [37]. Although the inclusion of viral loads reported at specific assay detection limits in the category ‘50–399 copies/ml’ could have meant we underestimated the true MTCT rate among women with actual viral load measures between 50 and 399 copies/ml, excluding values at these assay detection levels in fact led to slightly lower estimated MTCT rates in this group and did not substantially alter our findings. For some analyses, we excluded infants known or suspected to have been breastfed (about 0.5% of all infants), but it is possible that some breastfed infants were not excluded. Our data should, therefore, not be used to derive MTCT rates among breastfeeding women, or breastfeeding rates among HIV-positive women in this population.

Virtual elimination of MTCT is a global target. Our findings demonstrate that an MTCT rate of 0.5% can be achieved at a population level, which suggests that consideration could be given to redefining future virtual elimination targets as less than 0.5% rather than less than 2% for nonbreastfeeding settings [38]. Our results also serve to highlight the extensive inequities in access to PMTCT interventions, both between world regions and within them. In the UK, most pregnant women with HIV are diagnosed and 99% of these now receive cART, whereas UNAIDS estimates that coverage with effective regimens for PMTCT is only 27% in west and central Africa [39]. Meanwhile, MTCT rates in parts of eastern Europe are four to 10 times higher than in the UK, reflecting poorer access to cART and the challenges of delivering optimal PMTCT services to socially disadvantaged women such as injecting drug users [9].

It remains to be seen whether MTCT rates in the UK and Ireland will continue to decline, given increasing numbers of pregnant women with lengthy and complex treatment histories. Most of the 29 HIV-infected infants born to diagnosed women in 2007–2011 had risk factors such as insufficient antenatal ART, high maternal viral load despite cART (indicating adherence problems or drug resistance), very preterm delivery, or a combination of these factors. Ensuring that new infant infections are averted in the future remains a priority and requires ongoing close monitoring [40]. Continued early testing for HIV in pregnancy combined with careful management, appropriate support, and prompt initiation of cART, particularly for women with high viral loads, will be essential to maintaining these low MTCT rates. Efforts to promote HIV testing in the general population to facilitate early diagnosis will also be key, together with retention in HIV care of diagnosed individuals. For the 99.5% of uninfected infants, continued vigilance with respect to potential risks of in-utero exposure to maternal HIV and ART is also important.


National surveillance of obstetric and pediatric HIV is undertaken through the National Study of HIV in Pregnancy and Childhood (NSHPC) in collaboration with the Health Protection Agency Centre for Infections, now Public Health England, and Health Protection Scotland. The authors gratefully acknowledge the contribution of the midwives, obstetricians, genitourinary physicians, pediatricians, clinical nurse specialists, and all other colleagues who report to the NSHPC through the British Paediatric Surveillance Unit of the Royal College of Paediatrics and Child Health, and the obstetric reporting scheme run under the auspices of the Royal College of Obstetricians and Gynaecologists. They also thank Icina Shakes and Kate Francis (Study Assistants), Helen Peters and Angela Jackson (Research Assistants), and Clare French (Medical Research Council PhD student) for their essential contributions to the NSHPC, and Jenny Tosswill (Public Health England) for supplementing data on infection status. They would also like to acknowledge the invaluable contribution of their colleague and greatly missed friend Janet Masters, NSHPC data manager and coordinator for many years, who died in December 2012. Tribute at www.nshpc.ucl.ac.uk/nshpc/jmasters.

The National Study of HIV in Pregnancy and Childhood has London Multi-Centre Research Ethics Committee approval (MREC/04/2/009).

C.L.T. and M.C.B. carried out the statistical analyses. All authors contributed to developing the concept of the article, interpreting the results, and critically revising the article, and all authors approved the final version. P.A.T. is responsible for the NSHPC and is the guarantor.

The National Study of HIV in Pregnancy and Childhood receives core funding from the Health Protection Agency (grant number GHP/003/013/003), with additional funding from the National Screening Committee and the Welton Foundation. This work was undertaken at the Centre for Paediatric Epidemiology and Biostatistics, University College London (UCL), which benefited from funding support from the Medical Research Council (MRC) in its capacity as the MRC Centre of Epidemiology for Child Health (grant number G0400546). The UCL Institute of Child Health receives a proportion of funding from the Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme. C.T. was funded by the Wellchild Trust through a Research Training Fellowship, and L.B. is funded by an MRC Clinical Research Training Fellowship.

Conflicts of interest

C.L.T. received personal fees from the UK National Screening Committee and Biotest AG; C.T. received grants from the European Union FP7, UK National Screening Committee, PENTA Foundation, UNICEF, AbbVie, and ViiV; A.dR. received personal fees from Gilead, Janssen, ViiV, and Merck (MSD); P.A.T. received grants from the UK National Screening Committee, PENTA Foundation, AbbVie, and IATEC/Kendle, and personal fees from the UK National Screening Committee and Nutricia; G.T., A.dR., and P.A.T. are members of the Writing Group for the British HIV Association's Guidelines for the Management of HIV Infection in Pregnant Women.


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antiretroviral agents; antiretroviral therapy; highly active; HIV; infectious disease transmission; pregnancy; vertical; viral load

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