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Keywords:

  • Antenatal;
  • HIV;
  • pregnancy;
  • prevention

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Untreated HIV leads to poorer maternal and infant outcomes
  5. Does ART improve maternal and infant outcomes?
  6. Pre-term delivery may be associated with highly active ART
  7. HIV counselling and testing during pregnancy
  8. Repeat HIV testing is important to detect HIV infection acquired during pregnancy
  9. Mother-to-child transmission
  10. Resource-rich approach to the reduction of MTCT
  11. Resource-poor setting approach to the reduction of MTCT
  12. Health systems research
  13. Conclusion
  14. References

Please cite this paper as: Mepham S, Bland R, Newell M-L. Prevention of mother-to-child transmission of HIV in resource-rich and -poor settings. BJOG 2011;118:202–218.

Without prevention, a third of HIV-exposed infants acquire HIV in breastfeeding populations before, during, or after delivery through mother-to-child transmission (MTCT). Whereas MTCT is now a sentinel event in resource-rich countries with antiretroviral prophylaxis, caesarean section, and avoidance of breastfeeding, this is not yet the case in resource-poor settings because breastfeeding is crucial to infant survival. Recent advances in postpartum maternal and infant prophylaxis enables safer breastfeeding, and increasing numbers of women accessing treatment and prevention of MTCT services in sub-Saharan Africa is leading to optimism that MTCT could be eliminated here also, as reflected in the UNAIDS target of 2015.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Untreated HIV leads to poorer maternal and infant outcomes
  5. Does ART improve maternal and infant outcomes?
  6. Pre-term delivery may be associated with highly active ART
  7. HIV counselling and testing during pregnancy
  8. Repeat HIV testing is important to detect HIV infection acquired during pregnancy
  9. Mother-to-child transmission
  10. Resource-rich approach to the reduction of MTCT
  11. Resource-poor setting approach to the reduction of MTCT
  12. Health systems research
  13. Conclusion
  14. References

By end 2008, an estimated 33.4 million (31.1–35.8 million) people were living with HIV, two-thirds in sub-Saharan Africa, including an estimated 2.1 million (1.2–2.9 million) children under the age of 15.1 Whereas mother-to-child-transmission (MTCT) has been virtually eliminated in North America and Western Europe,1 390 000 (210 000–570 000) children are infected each year in sub-Saharan Africa, with 90% as a result of MTCT.1 In 2005 in rural KwaZulu-Natal, South Africa, the overall prevalence at the first antenatal clinic (ANC) visit was 37.7%, with a peak prevalence of 54.3% in women aged 25–29 years of age.2 Incidences during pregnancy reach between 1.6 and 2.3 in East Africa,3,4 and up to 10.7 per 100 woman years in KwaZulu-Natal, South Africa.5 In the UK, although the overall antenatal prevalence in 2008 was low, at 0.2%, the rate was higher within London (0.45%), especially in women originating from sub-Saharan Africa (2.5%).6 HIV is the leading cause of death in women of reproductive age worldwide.7

This paper reviews the many challenges that HIV poses in pregnancy in resource-rich and -poor settings, including effects on pregnancy and pregnancy outcomes, diagnosis, treatment for the health of the mother, prevention of mother-to-child-transmission (PMTCT), and implementation of strategies to support optimal infant feeding. Significant changes have occurred recently to WHO guidelines,8,9 with infant and postpartum maternal prophylaxis now recommended to support and reduce the risk of breastfeeding, as well as the commencement of antenatal antiretroviral therapy (ART) at an earlier gestation, and at a higher cluster of differentiation 4 (CD4) count, than in previous years. These advances, potentially reducing the risk of MTCT to under 5%, coupled with a rapid expansion in PMTCT coverage in sub-Saharan Africa, has led to renewed optimism that MTCT in resource-poor settings could potentially be eliminated in 5 years. Such an aim is ambitious but crucial if we are to meet the United Nations Millennium Development Goals relating to infant mortality, maternal health, and HIV/AIDS by 2015.10

Untreated HIV leads to poorer maternal and infant outcomes

  1. Top of page
  2. Abstract
  3. Introduction
  4. Untreated HIV leads to poorer maternal and infant outcomes
  5. Does ART improve maternal and infant outcomes?
  6. Pre-term delivery may be associated with highly active ART
  7. HIV counselling and testing during pregnancy
  8. Repeat HIV testing is important to detect HIV infection acquired during pregnancy
  9. Mother-to-child transmission
  10. Resource-rich approach to the reduction of MTCT
  11. Resource-poor setting approach to the reduction of MTCT
  12. Health systems research
  13. Conclusion
  14. References

HIV leads to poorer maternal and infant outcomes as a consequence of both HIV per se and HIV infectious complications.11 A retrospective review (2003–2007) of clinical notes in a tertiary referral centre in Johannesburg revealed that HIV-infected women had a 6.2-fold (95% CI 3.6–11.4) higher risk of death compared with HIV-uninfected women, most commonly secondary to tuberculosis (31%, 18/59) and pneumonia (20%, 12/59).1 Despite some methodological caveats associated with earlier cohort studies,13 general consensus agrees that maternal HIV infection is associated with an increased risk of antenatal death,14 spontaneous abortion,13,14 stillbirth,13,14 low birthweight (LBW, <2500 g) infants,13,14 small-for-gestational-age infants,15 and preterm birth.15

Does ART improve maternal and infant outcomes?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Untreated HIV leads to poorer maternal and infant outcomes
  5. Does ART improve maternal and infant outcomes?
  6. Pre-term delivery may be associated with highly active ART
  7. HIV counselling and testing during pregnancy
  8. Repeat HIV testing is important to detect HIV infection acquired during pregnancy
  9. Mother-to-child transmission
  10. Resource-rich approach to the reduction of MTCT
  11. Resource-poor setting approach to the reduction of MTCT
  12. Health systems research
  13. Conclusion
  14. References

There is limited evidence at a population level regarding a reduction in the mortality of HIV-infected mothers following the use of ART, probably because until recently treatment eligibility has been restricted to advanced disease only, and PMTCT prophylaxis has been limited to one drug administered later in pregnancy. No change was seen in the rate of maternal complications following the roll-out of ART in a tertiary referral hospital in Johannesburg.12 However, in rural KwaZulu-Natal, the roll-out of a district-wide HIV treatment programme resulted in a significant reduction in age-standardised mortality in women aged 25–49 years from 22.52 to 17.58 per 1000 woman-years (95% CI 0.691–0.881, P < 0.001).16,17 Maternal survival is critical to the survival of young children:18,19 infants of women receiving ART had a 75% reduction in mortality rates by the age of 5 years compared with those belonging to women who were not on ART, as a result of the improved survival of HIV-infected mothers.20

Pre-term delivery may be associated with highly active ART

  1. Top of page
  2. Abstract
  3. Introduction
  4. Untreated HIV leads to poorer maternal and infant outcomes
  5. Does ART improve maternal and infant outcomes?
  6. Pre-term delivery may be associated with highly active ART
  7. HIV counselling and testing during pregnancy
  8. Repeat HIV testing is important to detect HIV infection acquired during pregnancy
  9. Mother-to-child transmission
  10. Resource-rich approach to the reduction of MTCT
  11. Resource-poor setting approach to the reduction of MTCT
  12. Health systems research
  13. Conclusion
  14. References

The potential association between combination ART and preterm labour (at <37 weeks of gestation) has been known for over 12 years. Some studies showed a link,21–24 and others showed no effect,25–27 with differences between the populations and the lack of control for confounding factors making comparisons difficult.21–25 Subsequent studies have addressed these issues, and show a 1.4–3.4-fold increased risk of preterm delivery compared with zidovudine (ZDV) monotherapy in those taking highly active ART (HAART), with or without a protease inhibitor (PI).28–31 Although the benefits of HAART in reducing MTCT risk outweigh the potential adverse effects in most resource-rich settings, women should be counselled about the potential risks of starting HAART during pregnancy,28,30 with ZDV monotherapy prophylaxis combined with caesarean section remaining an alternative option in some settings.28 With current WHO guidelines now recommending the use of HAART for many PMTCT scenarios,8,9 it remains uncertain what the potential effect might be of increased preterm deliveries in resource-poor settings where facilities to care for premature infants are limited.

One proposed mechanism to explain the phenomenon of HAART-induced premature delivery involves the reversal of the TH1 to TH2 cytokine switch that naturally occurs during pregnancy. Immunosuppressive TH2 cytokines such as IL10 and IL4 are produced by the fetoplacental unit to reduce cell-mediated activation and maintain the fetal ‘allograft’. Antiretrovirals act to promote type-1 cytokines, such as IL2 and γ-interferon, which may benefit the control of HIV disease, but could harm the viability of a pregnancy.32,33

HIV counselling and testing during pregnancy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Untreated HIV leads to poorer maternal and infant outcomes
  5. Does ART improve maternal and infant outcomes?
  6. Pre-term delivery may be associated with highly active ART
  7. HIV counselling and testing during pregnancy
  8. Repeat HIV testing is important to detect HIV infection acquired during pregnancy
  9. Mother-to-child transmission
  10. Resource-rich approach to the reduction of MTCT
  11. Resource-poor setting approach to the reduction of MTCT
  12. Health systems research
  13. Conclusion
  14. References

HIV testing and counselling in pregnancy is the gateway to effective treatment and support services. The WHO34 recommends access to an HIV test as early in pregnancy as possible, the result of which would allow women living with HIV to benefit from resources to minimise the risk of MTCT, whereas HIV-uninfected women can be supported to remain uninfected.11 Unfortunately, many women in low-resource parts of the world fail to benefit from this test,35 with the suggested reasons for this including poverty and difficulty in accessing health care, late presentation to antenatal services, stigma, mistrust in the reliability of the test, the need to discuss with a partner before testing, fear of the impact of obtaining a positive result such as potential domestic violence and ostracism, and lack of awareness of PMTCT interventions.36–43 Additionally, poor healthcare infrastructure, irregular supply of test kits, and inadequate numbers of healthcare professionals and counsellors also contribute to this problem.15,44 Addressing these issues is challenging, although improved test uptake has been demonstrated in some settings through the provision of couple counselling and testing,45–50 opt-out testing strategies (not successful in all cases43),51–53 on-site testing,43 high-quality counselling of pregnant women regarding the benefits of testing, increased availability of HIV testing services,43 point-of-care CD4 testing,54 promotion of PMTCT services to the public at all levels, and changing attitudes towards people living with HIV.53,55,56

Repeat HIV testing is important to detect HIV infection acquired during pregnancy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Untreated HIV leads to poorer maternal and infant outcomes
  5. Does ART improve maternal and infant outcomes?
  6. Pre-term delivery may be associated with highly active ART
  7. HIV counselling and testing during pregnancy
  8. Repeat HIV testing is important to detect HIV infection acquired during pregnancy
  9. Mother-to-child transmission
  10. Resource-rich approach to the reduction of MTCT
  11. Resource-poor setting approach to the reduction of MTCT
  12. Health systems research
  13. Conclusion
  14. References

Following HIV acquisition, HIV antibody tests may remain negative for 4–5 weeks.57 Evidence is accumulating reporting infant perinatal infection arising from maternal HIV infection acquired during pregnancy or the postpartum period.58–60 As some pregnant women are at increased risk of acquiring HIV during pregnancy as a consequence of concurrent sexually transmitted infections (STIs), intravenous drug abuse, or multiple partners,61 enhanced HIV testing strategies should be considered, especially in parts of the world where HIV is common.3–5 With high maternal RNA viral load at the time of delivery acting as a major risk factor in transmission,62,63 it seems likely that the MTCT rate will be increased during the high viral loads associated with primary HIV infection (PHI).64 As such, early PHI detection permits the timely initiation of appropriate HIV clinical management, resulting in a longer potential duration of PMTCT ART, thereby reducing the risk of MTCT.65

Antenatal testing for HIV usually consists of an antibody-based test followed, if positive, by a confirmatory antibody test. Sensitive and specific laboratory based third or fourth generation ELISA assays (the latter including the p24 antigen) tend to be used in resource-rich settings,66 whereas rapid antibody test kits tend to be used in the field in resource-poor countries. Reports of reduced rapid HIV test performance because of decreased sensitivity when used in the field (87.5–94.5%),67 as well as increased antenatal indeterminate test results compared with non-pregnant women,68 are potentially cause for concern for antenatal HIV testing programmes. In view of this, it has been shown that HIV detection may be improved if a second rapid test is used in parallel for all tests, not just as confirmation of a positive result.57,69,70 Another approach adopted by a number of high- and low-resource countries has been a two-stage testing strategy, with a repeat test in the third trimester to detect HIV acquisition subsequent to an antenatal negative HIV antibody test.5,71,72 In the UK, with a low prevalence, universal re-testing is not part of standard guidelines,73 although it is recommended for high-risk individuals.74 In high-prevalence settings, rapid HIV testing in women of uncertain HIV status presenting in labour has proved feasible and cost-effective in some cases,44,75,76 with others reporting low uptake, which might be increased by an opt-out approach.77 In areas of high HIV prevalence universal HIV antibody testing of infants at the 6-week immunisation visit not only detects HIV-exposed infants and, by inference, maternal infection, but also provides public health systems with an excellent tool to measure the effectiveness of PMTCT programmes.56,78 In non-pregnant, HIV-antibody-negative individuals, nucleic acid amplification techniques (NAAT) have been used to improve the detection of PHI in high- and low-resource settings.57,79–82 In an approach similar to the way that blood transfusion services screen for HIV, the cost-effectiveness of NAAT may be improved by pooling the serum of many individuals to screen for the presence of HIV RNA, with a positive result then prompting individual testing of each sample.

Mother-to-child transmission

  1. Top of page
  2. Abstract
  3. Introduction
  4. Untreated HIV leads to poorer maternal and infant outcomes
  5. Does ART improve maternal and infant outcomes?
  6. Pre-term delivery may be associated with highly active ART
  7. HIV counselling and testing during pregnancy
  8. Repeat HIV testing is important to detect HIV infection acquired during pregnancy
  9. Mother-to-child transmission
  10. Resource-rich approach to the reduction of MTCT
  11. Resource-poor setting approach to the reduction of MTCT
  12. Health systems research
  13. Conclusion
  14. References

Worldwide in 2008, 430 000 (240 000–610 000) children under the age of 15 were newly infected with HIV.1 Around 35% of exposed infants can become infected with HIV by the age of 2 years, with transmission occurring in utero, during labour, and postpartum as a result of breastfeeding.83 The risk of transmission increases with a low maternal CD4 count,84,85 maternal high viral load,86–91 concurrent STIs,92 maternal tuberculosis,93 prolonged rupture of membranes,92,94 vaginal delivery (as opposed to caesarean section),95,96 breastfeeding duration,97,98 mixed breastfeeding,99,100 high breast-milk RNA levels,86 and maternal mastitis.86,101,102 As antiretroviral regimens to reduce peripartum transmission have become widely available in low-resource, high-HIV-prevalent areas, the reduction of transmission through breastfeeding has become the focus of recent research and policy development.8,9

Resource-rich approach to the reduction of MTCT

  1. Top of page
  2. Abstract
  3. Introduction
  4. Untreated HIV leads to poorer maternal and infant outcomes
  5. Does ART improve maternal and infant outcomes?
  6. Pre-term delivery may be associated with highly active ART
  7. HIV counselling and testing during pregnancy
  8. Repeat HIV testing is important to detect HIV infection acquired during pregnancy
  9. Mother-to-child transmission
  10. Resource-rich approach to the reduction of MTCT
  11. Resource-poor setting approach to the reduction of MTCT
  12. Health systems research
  13. Conclusion
  14. References

Highly successful interventions employed in resource-rich countries, including the use of HAART,26,103,104 targeted elective caesarean sections,95 and the avoidance of breastfeeding,83 have reduced transmissions to under 2%.105 Current UK and US guidelines recommend that in addition to standard antenatal care, HIV-infected pregnant women should be screened for opportunistic infections, STIs, syphilis, and other blood-borne viruses, for example hepatitis B virus (HBV) and hepatitis C virus (HCV).74,106 Baseline investigations should include a full blood count and biochemical screen, CD4 count, HIV resistance testing, and an HIV RNA viral load.74,106 Women who fulfil the criteria for starting ART for their own health, currently a CD4 under 350 cells/ml or clinical stage-4 diagnosis,107 should be start on triple ART as soon as is practicable. This usually consists of two nucleoside reverse transcriptase inhibitors (NRTIs) plus one non-nucleoside reverse transcriptase inhibitor (NNRTI) or PI. In view of its central role in most antiretroviral trials, as well as being the only antiretroviral specifically indicated for use in pregnancy in the UK,74 ZDV should ideally be included as part of any treatment regimen.106 The drug choices are the same as for non-pregnant individuals, but with some caveats (Table 1).

Table 1.   A summary of recommendations, side effects, and cautions related to antiretroviral use in pregnancy106
Side effects/concerns
NRTIs Recommended: ZDV, 3TC. Alternative: Abacavir (ABC), Didanosine (DDI), FTC, Stavudine (D4T)
AnaemiaZidovudine is associated with anaemia and neutropenia in women and infants112
Mitochondrial toxicityAll NRTI drugs associated with neuropathy, myopathy, cardiomyopathy, pancreatitis, hepatic steatosis, and lactic acidosis. Combinations of D4T and 3TC,172 and D4T and DDI,173 have been particularly associated with severe life-threatening lactic acidosis in pregnancy
HypersensitivityAbacavir (5–8% of non-pregnant individuals; check HLA B*5701)
Hepatitis B co-infection3TC and Tenofovir: may result in liver function flare following ART cessation in HBV/HIV co-infected patients
Limited experience in pregnancyTenofovir: potential fetal bone effects. Included as first line in WHO guidelines9
NNRTIs Recommended: NVP
EFV-induced teratogenicityEFV should be avoided in the first trimester because of significant fetal malformations in 3/20 monkeys in preclinical studies.174 Use in the second trimester may be considered if there are no other alternatives. Many clinicians would continue the drug if pregnancy has occurred whilst on EFV and the woman is into her second trimester175,176
NVP-induced hepatotoxicityWomen with a CD4 > 250 cells/ml are at an increased risk of potentially life-threatening NVP-induced hepatotoxicity and rash. NVP should only be started in these circumstances when the benefits outweigh the risks in conjunction with frequent monitoring of liver function177,178
Limited experience in pregnancyEtravirine
PIs, entry inhibitors, and integrase inhibitors Recommended: Lopinavir/ritonavir. Alternative: Atazanavir/ritonavir, Indinavir/ritonavir, Nelfinavir, Ritonavir, Saquinavir/ritonavir
HyperglycaemiaWhereas PIs may cause hyperglycaemia, there is no evidence that their use in pregnancy confers any additional risk179
Lopinavir/ritonavir formulationPharmacokinetic studies are ongoing with a new tablet formulation, which may require a dosage increase in the third trimester. Current advice is to use existing capsule formulation until this is resolved
No experience in pregnancyPIs: Darunavir, Fosamprenavir, Tipranavir. Entry inhibitors: Enfurvirtide and Maraviroc. Integrase inhibitor: Raltegravir176

Advice for women with less advanced disease requiring prophylactic PMTCT therapy varies: US 2009 guidelines advocate the use of triple therapy for all,106 whereas British HIV Association (BHIVA) Guidelines 2008,74 mindful of potential preterm delivery issues with HAART regimens,21–24,28–31,108 provide two alternative regimens that can be considered. ZDV monotherapy (similar to the PHPT2 study;65Table 2) is suggested for women with low viral loads (<10 000 copies/ml), no resistance mutations, and who are willing to have an elective caesarean section, whereas triple therapy can be considered for those with high viral loads (>10 000 copies/ml), and/or those with resistance mutations or those unwilling to consider a caesarean section. Current WHO guidelines recommending the commencement of ART from as early as 14 weeks of gestation, on the grounds that a longer course of ARVs reduces in utero transmission (Table 2),8,9,65,109 are likely to influence future BHIVA guidelines, which currently recommend commencement at 28 weeks of gestation for women at low risk of transmitting. Despite the absence of firm evidenced-based guidance, those failing to fully suppress their viral load (BHIVA) or with over 1000 copies/ml (USA) by 36 weeks of gestation are offered an elective caesarean section at 38 weeks of gestation.74,106

Table 2.   Evidence regarding the prevention of in utero and intrapartum MTCT
Selected antiretroviral studiesSample size arm/arm (Total)ComparisonStudy descriptionBF/RFIntervention (95% CI; where listed)Comparison (95% CI; where listed)ReductionP
  1. BF, breastfeeding; RF, replacement feeding.

  2. *ACTG 316, trial terminated early because of lower than expected transmission rates.

  3. **PHPT-1, short–short arm was discontinued during the interim analysis (inferiority).

  4. ***PHPT-2, placebo–placebo ‘NVP’ arm terminated during an interim analysis because of inferiority.

Zidovudine monotherapy throughout pregnancy and delivery
PACTG 076112 (USA)180/183ZDV versus placeboFrom 14 weeks antepartum, ZDV during delivery (i.v.); 6 weeks infantRF8.325.5670.001
Combination Antiretrovirals
ANRS 07526 (France)445/899ZDV/3TC versus ZDV (historical control)ZDV from 14 weeks of gestation/3TC from 32 weeks of gestation; infants 3TC 6 weeksRF1.66.876<0.001
WITS, observational cohort103710ZDVObservational studyRF10.4 (8.2–12.6)Reference arm
186/710Dual therapy versus ZDVObservational studyRF3.8 (1.1–6.5)10.4OR 0.330.03
250/710HAART versus ZDVObservational studyRF1.2 (0–2.5)10.4OR 0.150.002
ACTG 316104642/628ZDV or Dual or HAART Plus NVP or placeboObservational study. Maternal ARVs; NVP to mother and infantRF1.4*1.60NS
Short-course ARVs versus placebo
DITRAME118 (Ivory Coast, Burkina Faso)192/197 (421)ZDV versus placeboFrom 36 weeks antenatal to intrapartum; 7 days ZDV postpartum (mother)RF18.027.535 (0.05–0.60) 6 months MTCT rate0.027
RETRO CI120 (Ivory Coast)140/140 (280)ZDV versus placeboFrom 36 weeks antepartum to intrapartumBF12.2 (6.2–17.8)21.7 (14.0–28.8)44 (4 weeks MTCT rate)0.05
PETRA121 (Tanzania, Uganda, South Africa)475/371 (1797)ZDV/3TC versus placebo PETRA AFrom 36 weeks antepartum (mother); 1 week infant, 1 week postpartum (mother)BF5.715.363 (35–79) 6 weeks MTCT rate0.001
474/371 (1797)ZDV/3TC versus placebo PETRA BIntrapartum (mother); 1 week infant; 1 week postpartum (mother)BF8.915.342 (6–64) 6 weeks MTCT rate0.016
471/371 (1797)ZDV/3TC versus placebo PETRA CIntrapartumBF14.215.30 (6 weeks MTCT rate)NS
Longer course versus short course
PHPT-165 (Thailand)419ZDV: Long–long armFrom 28 weeks antepartum; 6 weeks infantRF6.5 (4.1–8.9)Reference arm
350/419ZDV: Long–short armFrom 28 weeks antepartum; 3 days infantRF4.7 (2.4–7.0)6.5 (4.1–8.9)28NS
345/419ZDV: Short–long armFrom 35 weeks antepartum; 6 weeks infantRF8.6 (5.6–11.6)6.5 (4.1–8.9)0NS
323/419ZDV: Short–short armFrom 35 weeks antepartum; 3 days infant**RF10.5 (6.4–14.4)6.5 (4.1–8.9)0
1437 (all)ZDV: pooled Analysis(Long–long PLUS long–short) versus (short-long PLUS short–short). 6 months MTCT rateRF1.6 (0.7–2.6)5.1 (3.2–7.0)69<0.001
Bhoopat et al.122 (Thailand)23/27ZDV (long) versus ZDV (short)ZDV 62–92 days antenatally versus ZDV 14–35 days antenatally. HIV-1 detected in placental tissue226767<0.02
Intrapartum NVP
HIVNET 012123,124 (Uganda)308/310 (626)sd-NVP versus ZDV200 mg intrapartum; 2 mg/kg NVP infant within 72 hours versus maternal ZDV 300 mg 3-hourly until delivery; neonatal ZDVBF11.9 (8.2–15.7)21.3 (16.4–26.2)44 (8 weeks)0.003
15.7 (11.5–19.8)25.8 (20.7–30.8)39 (18 month MTCT rate)0.0023
SAINT125 (South Africa)662/657 (1317)Intrapartum maternal/infant ZDV/3TC v Maternal/infant NVPIntrapartum maternal multiple dose ZDV/3TC; maternal/infant ZDV/3TC 1 week versus intrapartum maternal sd-NVP; infant sd-NVP within 24–48 hoursBF9.3 (7.0–11.6)12.3 (9.7–15.0)23 (8 weeks MTCT rate)NS
Zidovudine combined with NVP
PHPT-2109 (Thailand)724/721 (1844)ZDV/NVP–NVP versus ZDV/NVP–placebo versus ZDV/placebo–placebo***ZDV from 28 weeks antepartum; NVP intrapartum (maternal); NVP (infant)RF1.1 (0.3–2.2) NVP–NVP6.3 (3.8–8.9) Placebo/placebo83 (6 months MTCT rate)<0.001

Elective caesarean section at 38 weeks gestation was associated with an 80% risk reduction of MTCT at 6 weeks postpartum, when compared with spontaneous vaginal delivery in a randomised controlled trial (1.8 versus 10.5%; OR 0.2, 95% CI 0.1–0.6, < 0.001).95 However, as caesarean section is not a risk-free intervention in HIV-infected women,110 attempts have been made to determine which women would particularly benefit from it. Whereas viral load is an important risk factor for MTCT, included in the guidelines as part of practical recommendations, no study has yet shown that viral load suppression removes the MTCT risk associated with a vaginal delivery. A recent observational cohort showed a significantly lower risk of MTCT in women with delivery viral loads of under 400 copies/ml who had an elective caesarean section, compared with vaginal delivery (AOR 0.2, 95% CI 0.05–0.65),111 but lacked statistical power to shed light on delivery choices in women with undetectable viral loads.111

Intrapartum intravenous ZDV (similar to PACTG 076;112Table 2) is suggested by the US 2009 guidelines for all deliveries on the grounds that is safe and effective,106 whereas BHIVA74 guidelines limit its use to women taking ZDV monotherapy, ART for their own health, and those without full viral load suppression. Untreated women presenting in labour are given ongoing nevirapine (NVP)-based HAART,74 or intravenous ZDV plus either single dose nevirapine (sd-NVP) with 1 week of ZDV/lamivudine (3TC),106 with the latter provided to minimise the risk of postpartum development of NVP mutations. Women stopping an NVP-based prophylactic triple therapy after delivery are advised to stop the NVP at least 7 days before the NRTI backbone, in view of the long NVP half life and risk of inadvertent NVP monotherapy and subsequent NVP mutations.106 Recent work has provided reassurance that those stopping PI-based HAART prophylaxis have a minimal risk of subsequent PI resistance.113

All infants are advised to receive replacement feeding, where safe and affordable to do so. Infants whose mothers have a suppressed viral load on HAART, or are receiving a combination of ZDV monotherapy, intravenous ZDV, and an elective caesarean section, are advised to receive ZDV monotherapy prophylaxis for 4 or 6 weeks.74,106 For infants with a mother on HAART and a detectable viral load, triple therapy for 4 or 6 weeks is recommended.74,106

Resource-poor setting approach to the reduction of MTCT

  1. Top of page
  2. Abstract
  3. Introduction
  4. Untreated HIV leads to poorer maternal and infant outcomes
  5. Does ART improve maternal and infant outcomes?
  6. Pre-term delivery may be associated with highly active ART
  7. HIV counselling and testing during pregnancy
  8. Repeat HIV testing is important to detect HIV infection acquired during pregnancy
  9. Mother-to-child transmission
  10. Resource-rich approach to the reduction of MTCT
  11. Resource-poor setting approach to the reduction of MTCT
  12. Health systems research
  13. Conclusion
  14. References

Many of the costly and complex interventions available in resource-rich settings are unaffordable or not feasible in a developing world setting. The complete avoidance or shortening of breastfeeding by HIV-infected women in many parts of the world exposes infants to risks, including life-threatening infections and malnutrition as a result of inadequate replacement feeding.114–117 Recent evidence from randomised trials have led to changes to the WHO guidelines,8,9 such that the previous short course regimens that did little to prevent postpartum transmission have been replaced by a longer course of antenatal ART starting earlier in pregnancy, a higher CD4 threshold for the commencement of HAART for women requiring treatment for her own health, and maternal or infant ART prophylaxis during the breastfeeding period.

Pregnant women receiving HAART for their own health in a resource-poor setting

The WHO now recommends an increased CD4 threshold for eligibility of a pregnant women to commence lifelong ART from <200 cells/mm3 to <350 cells/mm3, or clinical stages 3 or 4.8,9 The choice of combination ART follows similar principles as for resource-rich settings, and although the absolute drug choices will vary locally according to cost and availability, the WHO recommends the inclusion of a ZDV (or Tenofovir, TDF) and 3TC (or Emtricitabine, FTC) backbone, plus either NVP or, with some caveats, efavirenz (EFV) (Table 1). Both breastfed and formula-fed infants are recommended to receive 6 weeks of prophylaxis. Although strong evidence exists for the use of NVP during breastfeeding, either NVP or ZDV may be used for formula-fed infants.8,9

PMTCT prevention strategies in a resource-poor setting

Early prophylaxis trials were effective at reducing the in utero and peripartum MTCT of HIV. They demonstrated that ZDV monotherapy was superior to placebo,118–121 that ART started from 28 weeks of gestation was superior to starting at 36 weeks of gestation,65,122 that sd-NVP at the time of labour given to both mother and child was simple, with immediate (11.9 versus 21.3%) and durable (15.7 versus 25.8%; 18 months) effects when compared with intrapartum ZDV or ZDV/3TC,123–125 and that maternal ZDV starting at 28 weeks of gestation combined with maternal and infant sd-NVP was superior to ZDV alone (1.9 versus 6.3%).109 Despite these advances, significant shortcomings continued to exist, including the subsequent development of ARV resistance,126–133 and, most importantly, the failure to address the issue of postpartum transmission as a result of breastfeeding.119,121,134

Single-dose nevirapine is associated with significant postpartum resistance

A meta-analysis of studies using sd-NVP found an NVP resistance prevalence of 35.7% in mothers and 52.6% in infants.126 Because NVP resistance occurs as a consequence of its long excretory half-life, the emergence of resistance could be reduced if a 3-day postpartum ‘tail’ of ZDV/3TC followed sd-NVP [4.3% (3/69), 95% CI 0.9–12.2%, versus 38.1% (16/42), 95% CI 23.6–54.4% without a postpartum tail).130 The addition of 7 days of ZDV to sd-NVP for infants led to lower NVP resistance at 6–8 weeks than in infants who had not received ZDV [4/15 (27%) versus 20/23 (87%), < 0.01].133

Supporting breastfeeding with strategies to reduce postpartum transmission

Breastfeeding is crucial to the survival of infants in resource-constrained environments.83,114,115,135–138 Benefits include protection against infection (notably diarrhoea, pneumonia, neonatal sepsis, and otitis media) and the transfer of passive immunity and nutrition;139 exclusive breastfeeding also helps mothers to space their pregnancies.83 However, breastfeeding by HIV-infected mothers exposes infants to HIV.83

Whereas many short-course regimens have been successful in reducing peripartum transmission, there is often no improvement in the HIV-uninfected infant survival rate at 2 years as a result of infectious illness and malnutrition following the rapid cessation of breastfeeding, or HIV infection through breastfeeding.119,121 The MASHI study (Botswana),134 which randomised infants taking 1 month of oral ZDV to receive either breastfeeding or formula milk for 6 months, showed that although the formula arm resulted in fewer HIV infections at 7 months, the combined mortality and HIV infection between the arms at 18 months were similar (13.9 versus 15.1%).

Prophylactic strategies aiming to reduce postpartum HIV transmission whilst supporting breastfeeding can be divided into: (i) maternal ART (Table 3); (ii) infant ART (Table 4); and (iii) non-ART infant-feeding interventions.

Table 3.   Studies of postpartum maternal ART prophylaxis in breastfeeding populations
Selected antiretroviral studiesSample size arm/arm (total)ComparisonStudy descriptionBF/RFIntervention (95% CI; where listed)Comparison (95% CI; where listed)ReductionP
  1. *MITRA PLUS, following the finding that women with higher CD4 counts have a higher risk of NVP-induced hepatotoxicity.

MITRA PLUS141 Observational (Tanzania)441 (total)ZDV/3TC/NVP (NVP replaced by NLF*)Maternal HAART from 34 weeks to 6 months postpartumBF5.0 (6 months)
Kisumu142 (Kenya)497 (total)ZDV/3TC/NVP (later Nelfinavir)Phase IIb single arm prevention study. HAART from 34 weeks of gestation to 6 months postpartum; CD4 > 250 cells/mm3. HIV transmission rates at 12 monthsBF5.9 (4.0–8.5)
Kesho Bora163 (multicentre)411/413 (855)ZDV/3TC/LPV/r v ZDV/sd-NVP/1 week ZDV/3TCMaternal HAART from 28 weeks of gestation until 6 months postpartum versus ZDV from 28 weeks of gestation until delivery, sd-NVP, and 1 week ZDV/3TC; CD4 200–500 cells/mm3; all infants sd-NVP PLUS 1 week ZDV. HIV-free survivalBF10.4 (7.7–13.9)16.3 (12.9–20.5)36%0.022
Mma Bana140 (Botswana)283/270 (553)ZDV/3TC/ABC v ZDV/3TC/LPV/rHAART commencing at 26–34 weeks of gestation, CD4 > 200 cells/mm3, until cessation of breastfeeding at 6 months. HIV infant infection at 6 monthsBF1.80.40.53
BAN153 (Malawi)2637Maternal HAART (ZDV/3TC/LPV/r) v Infant NVP versus Control (no ART)Maternal HAART versus maternal infant NVP versus control from birth in breastfeeding infants; CD4 > 250 cells/mm3; infant > 2500 g; HIV-free infant survival at 28 weeks in infants initially HIV-uninfected. All mothers received antenatal ZDV from 28 weeks of gestation and intrapartum sd-NVPBF4.7% (HAART)7.6%38%0.03
2.9% (NVP)7.6%62%0.0001
4.7% (HAART)2.9% (NVP)NS0.07
Table 4.   Studies of neonatal and infant ART prophylaxis in a breastfeeding population
Selected antiretroviral studiesSample size arm/arm (Total)ComparisonStudy descriptionBF/RFIntervention (95% CI, where listed)Comparison (95% CI, where listed)ReductionP
Short course neonatal prophylaxis
NVAZ148 (Malawi)484/468 (1119)NVP/ZDV versus NVPSingle dose NVP at birth; ZDV for 7 days postpartumBF15.320.927 (6 weeks MTCT rate)0.03
Taha et al.180 (Malawi)446/448 (894)Maternal NVP; neonatal NVP/ZDV versus NVP aloneMaternal NVP; single dose NVP at birth; ZDV for 7 days postpartumBF16.3 (12.7–19.8)14.1 (10.7–17.4)0 (6 weeks MTCT rate)0.30
Longer course neonatal prophylaxis
MASHI134 (Botswana)598/602 (1200)BF/ZDV versus RFMaternal ZDV from 34 weeks to intrapartum. Infant BF/ZDV, 6 months or replacement feeding/ZDV, 1 monthBF9.05.60 (7-month cumulative MTCT rate)0.04
598/602 (1200)BF/ZDV versus RFMaternal ZDV from 34 weeks to intrapartum. Infant BF/ZDV, 6 months or replacement feeding/ZDV, 1 monthBF15.113.90 (18 months death/HIV)0.6
MITRA144 (Tanzania)398/264Neonatal 3TCMaternal ZDV/3TC from 36 weeks to 7 days postpartum; neonatal ZDV/3TC 7 days with/without 6 months 3TCBF8.515.545 (6 months death/HIV)<0.001
SWEN145 (multicentre)977/1047Neonatal 6 weeks NVP versus sd-NVPIntrapartum sd-NVP (maternal); 6 weeks NVP or neonatal sd-NVPBF2.535.27OR 0.54 (6 weeks MTCT rate)0.009
PEPI146 (Malawi)1099/1088 (3016)Neonatal NVP (long)/ZDV (short) versus controlNVP 14 weeks/ZDV 7 days vesus sd-NVP/ZDV 7 days (control)BF5.2 (3.9–7.0)10.6 (8.7–12.8)51 (9-months MTCT rate)<0.001
1089/1088 (3016)Neonatal NVP (long)/ZDV (long) versus controlNVP 14 weeks/ZDV 14 weeks versus sd-NVP/ZDV 7 days (control)BF6.4 (4.9–8.3)10.6 (8.7–12.8)45 (9—months MTCT rate)0.002

Prophylactic maternal ART to prevent postpartum transmission

Current WHO advice recommends that HIV-infected women not eligible for HAART should commence PMTCT prophylaxis from 14 weeks of gestation.65,122 Two regimes are suggested: ZDV monotherapy from 14 weeks of gestation, sd-NVP and ZDV/3TC during labour and delivery, a 1-week ‘tail’ of ZDV/3TC to the mother, and NVP infant prophylaxis until 1 week after the cessation of up to 1 year of breastfeeding (option A); or triple therapy until 1 week after the cessation of breastfeeding combined with 6 weeks of infant NVP or ZDV (option B).

The principle of providing triple therapy to breastfeeding mothers at 26–34 weeks of gestation until 6 months postpartum has been reported to give transmission rates of between 1 and 5%.140–142 Preliminary results of a WHO-coordinated, randomised controlled trial, the Kesho Bora study,143 have demonstrated increased HIV-free survival in infants of women receiving HAART from 28 weeks until 6 months postpartum, compared with ZDV monotherapy from 28 weeks of gestation until delivery, sd-NVP, and a 1-week ‘tail’ of ZDV/3TC (10.4%, 95% CI 7.7–13.9 versus 16.3%, 95% CI 12.9–20.5; = 0.022). Infants received sd-NVP and 1 week of ZDV. With over three-quarters of the infants receiving breastmilk for a median of 21.4 weeks, infants in the short course were not covered by maternal ART. The reduction in the 12-month cumulative HIV infection rate as a result of HAART was most marked in women with lower CD4 counts of between 200 and 350 cells/mm3 (6.1 versus 11.1%, = 0.044), with no significant difference seen in women with a CD4 of 350–500 cells/mm3.

Infant prophylaxis

Infant prophylaxis offers the potential advantages of sparing antiretroviral exposure in women not eligible for HAART, of being cheap and easy to administer, and of allowing the promotion of optimal infant feeding practices. Current WHO guidelines,8,9 based on infant prophylaxis trials (Table 4),134,144–147 advise that infants of breastfeeding mothers who received ZDV prophylaxis in pregnancy should receive NVP monotherapy until 1 week after the cessation of up to 1 year of breastfeeding, whereas all other HIV-exposed infants should receive a minimum of 6 weeks NVP with ZDV as an alternative for formula-fed infants.

Infant prophylaxis studies have demonstrated: the superiority of an additional 7-day course of ZDV when compared with sd-NVP alone (15.3 versus 20.9%);148 that 6 weeks of infant NVP was superior to sd-NVP (SWEN study, OR 0.54, 95% CI 0.34–0.85, = 0.009);145 and that 14 weeks of either NVP or NVP plus ZDV in breastfeeding infants of mothers who had not received any prophylaxis was superior at 9 months compared with sd-NVP and 7 days of ZDV (PEPI study, 5.2 versus 6.4 versus 10.6%; Table 4).146 Although effective and simple to implement, the risk of transmitting resistant virus to infants who become HIV-infected despite prophylaxis is of significant concern.149 HIV-infected infants who had received 6 weeks of NVP were significantly more likely to have an NVP resistance mutation compared with those receiving sd-NVP [92% (11/12) versus 38% (11/29), = 0.002).150 However, the concurrent use of ZDV for 14 weeks with 6 weeks of NVP significantly mitigated against NVP-resistant mutations compared with 6 weeks of NVP alone [62% (28/45) versus 86% (37/43), = 0.007).151 Results are awaited from the PROMISE-PEP study in breastfed infants, where boosted lopinavir,152 with its high barrier to the development of resistance, is being compared with 3TC, a drug with proven efficacy in reducing MTCT.144

With infant and maternal prophylaxis having similar aims, it is unclear which approach is superior in reducing postpartum MTCT whilst minimising the development of antiretroviral resistance. In the Breastfeeding, Antiretroviral, and Nutrition study (BAN),153 all mothers received antenatal ZDV/3TC and sd-NVP, and were randomised post delivery to either infant NVP, maternal HAART, or a control group for the duration of breastfeeding. Whereas the HIV-free infant survival at 6 months was significantly better in HIV-uninfected infants at birth taking prolonged NVP (2.9 versus 7.6% control group, < 0.0001), or in infants whose mothers were taking triple therapy (4.7 versus 7.6% control, = 0.03), no significant difference was seen between maternal HAART and infant NVP. Future studies comparing these two approaches are awaited, in particular the PROMISE study,154 where maternal HAART will be compared with infant NVP for the duration of the breastfeeding period.

Non-ART breastfeeding Interventions

The central theme of WHO guidance relating to infant feeding choices is to support the method that provides the greatest likelihood of infant HIV-free survival, whilst not harming maternal health.155 For this to happen, mothers should be counselled, supported, and advised of acceptable, feasible, affordable, sustainable, and safe (AFASS) infant feeding choices that best meets her needs. National and/or local policies should be principally developed to support HIV-infected mothers to breastfeed with ART interventions or breastfeeding avoidance, whilst not undermining optimal breastfeeding practices among the general population.

WHO breastfeeding advice recommends that HIV-uninfected mothers and those of unknown status are counselled to test for HIV, are shown how to remain HIV-uninfected, and are advised to exclusively breastfeed (where infants are given breastmilk only with no additional fluids or solids) for 6 months, introducing complementary foods thereafter, whilst continuing to breastfeed for 24 months or beyond.155 Identical advice is provided for HIV-infected women, except to recommend a reduced total breastfeeding duration of 12 months.

Exclusive breastfeeding (EBF) forms part of standard breastfeeding advice because it provides full nutrition for the infant, reduces the risk of diarrhoea and pneumonia-associated morbidity, compared with mixed feeding,156 and significantly reduces mastitis and other breast pathologies possibly caused by reduced milk stasis.101,157 Infants who exclusively breastfed had a significantly reduced MTCT when compared with those who also received solids in prospective observational cohorts in KwaZulu-Natal, South Africa (6-month MTCT rate HR 10.87, 95% CI 1.51–78.00, = 0.018), and in Zambia (4-month MTCT rate HR 3.48, 95% CI 1.71–7.08, = 0.004).99,158 Although EBF has been successfully implemented with community support in some settings,159–161 there has been some difficulty with uptake in higher HIV-prevalence areas,162 which is suggestive of cultural, community, and family pressures that dissuade women against EBF.157

The advent of successful post-partum ART strategies (Table 3),140–142,153,163 reducing the significant risk of late postpartum transmission,86,164 as well as the risks associated with the rapid cessation of breastfeeding,117 has led to significant changes in WHO advice,83 which previously restricted breastfeeding to 6 months. A randomised trial in Zambia compared HIV-infected women randomised to rapidly wean at 4 months with women who were supported to exclusively breastfeed for 6 months, with cessation of breastfeeding when they thought appropriate, after relevant counselling.117 No significant difference in the infant HIV-free survival was seen at 24 months (68.4 versus 64.0%, = 0.13), a result explained by the fact that 31% of the women in the rapid-weaning group continuing to breastfeed after 5 months as well as the relatively long median duration of 16 months to cessation of breastfeeding in the exclusive breastfeeding group. Additional deleterious effects to mothers in the rapid-weaning group were the additional cost of a milk-replacement as well as stigmatisation through the effective disclosure of their HIV status.117

Health systems research

  1. Top of page
  2. Abstract
  3. Introduction
  4. Untreated HIV leads to poorer maternal and infant outcomes
  5. Does ART improve maternal and infant outcomes?
  6. Pre-term delivery may be associated with highly active ART
  7. HIV counselling and testing during pregnancy
  8. Repeat HIV testing is important to detect HIV infection acquired during pregnancy
  9. Mother-to-child transmission
  10. Resource-rich approach to the reduction of MTCT
  11. Resource-poor setting approach to the reduction of MTCT
  12. Health systems research
  13. Conclusion
  14. References

According to the WHO, in 2008 an estimated 21% of pregnant women in low and middle-income countries received an HIV test,35 45% (37–57%) and 34% of eligible infected women received PMTCT prophylaxis or were assessed for ART for their own health, 32% of infants received ART prophylaxis, and 15% of children born to infected mothers received an HIV test within 2 months of birth.35 A further multicentre sub-Saharan study measuring NVP in neonatal cord blood from HIV-infected mothers and observing NVP administration showed that only 51% had taken the drugs correctly.165 Such attrition at each stage of the PMTCT testing and treatment cascade means that ultimately only a small proportion of HIV-infected women and their infants received optimum care. Quality service delivery requires the determination of underlying reasons for poor programme performance through audit, surveillance, monitoring, and evaluation.35,56,166–168 One highly effective approach in high-prevalence settings involves the universal HIV antibody testing of all infants presenting to the 6-week immunisation clinic, allowing the identification of HIV-exposed infants and subsequent investigation of infants failing to receive the correct intervention.56,78 To run effectively and sustainably, programmes should be integrated within existing antenatal and obstetric services, rather than running independently in a vertical fashion.169 Such services need to adopt the role of primary service provider of PMTCT services, and work closely alongside HIV and infant feeding counsellors, physicians, family planning and sexual health services, and civil society representatives of people living with HIV.170

The provision of 80% of HIV-infected women with effective PMTCT services has been the target commitment of at least five international accords, including the G8 (2005, 2007) and the UN General Assembly (2001, 2006), as well as prioritised action by UNAIDS, PEPFAR, and the Global Fund to Fight AIDS, TB, and Malaria.35 The commitment towards effective PMTCT services, combined with primary prevention of HIV infection amongst women of childbearing age, prevention of unintended pregnancies, and provision of appropriate HIV care, make up the four pillars of the UN comprehensive approach that has been adopted by many countries in their national HIV plan. The inclusion of PMTCT within these plans is crucial, and enables the government-driven coordination of different departments, numerical targets, standard packages of care, in line with international standards, and investment made in appropriate infrastructure.170 National governments need to train and retain medical staff as well as appropriate task-shifting to non-professional staff, whereas systems of procurement need to be strengthened to prevent drugs and other vital supplies running out of stock.170

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Untreated HIV leads to poorer maternal and infant outcomes
  5. Does ART improve maternal and infant outcomes?
  6. Pre-term delivery may be associated with highly active ART
  7. HIV counselling and testing during pregnancy
  8. Repeat HIV testing is important to detect HIV infection acquired during pregnancy
  9. Mother-to-child transmission
  10. Resource-rich approach to the reduction of MTCT
  11. Resource-poor setting approach to the reduction of MTCT
  12. Health systems research
  13. Conclusion
  14. References

Without interventions, over one-third of infants will be infected with HIV by 2 years of age, half of which as a result of breastfeeding. Early trials were successful at reducing in utero and peripartum transmission, but it is only recently that trials have shown the benefit of maternal and infant prophylaxis, allowing women to breastfeed safer, longer, and without the need for rapid weaning. What is currently unclear is how one or more courses of triple prophylaxis in subsequent pregnancies may affect maternal disease progression (early indications suggests that it does not),171 whether option A or option B prophylaxis in women with CD4 counts of >350 cells/mm3 is superior, and what the relative effectiveness of maternal prophylaxis during breastfeeding is compared with infant prophylaxis. Although MTCT is now a rare event in resource-rich countries, further work is needed to define which women can safely deliver vaginally, and to ensure that all women receive an HIV test, with some high-risk groups requiring an enhanced testing strategy. Although current PMTCT interventions worldwide fall short of the internationally agreed 80% coverage target, encouraging five-fold increases in PMTCT coverage have been seen in sub-Saharan Africa in the past 5 years, taking the coverage to around 40%. If the virtual eradication of new paediatric HIV infection is to be realised, UNAIDS estimates that an investment of $610 million per year will be required in low/middle-income countries, not only to improve and extend PMTCT services per se, but also to place them at the heart of comprehensive maternal, child, family planning, and sexual health services. At a time of increasing global fiscal austerity, such an ambition will be challenging. If it can be delivered, the return would be immeasurable.

Disclosure of interests

No conflicts of interest.

Contribution to authorship

SM, lead author; RB, critical review, paper layout; M-L Newell, critical review, paper layout.

Details of ethics approval

No ethical approval required.

Funding

No funding was sought.

Acknowledgements

None.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Untreated HIV leads to poorer maternal and infant outcomes
  5. Does ART improve maternal and infant outcomes?
  6. Pre-term delivery may be associated with highly active ART
  7. HIV counselling and testing during pregnancy
  8. Repeat HIV testing is important to detect HIV infection acquired during pregnancy
  9. Mother-to-child transmission
  10. Resource-rich approach to the reduction of MTCT
  11. Resource-poor setting approach to the reduction of MTCT
  12. Health systems research
  13. Conclusion
  14. References
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