HIV and pregnancy

Virginia Furner : The Albion Centre, Sydney, NSW

Women with human immunodeficiency virus (HIV) infection in Australia are now choosing pregnancy as a proactive, positive, reproductive option. There are, however, a number of women who will be initially diagnosed as having HIV infection during a pregnancy; these women should have access to all the recommended strategies to prevent mother-to-child transmission. In Australia, fourteen women during the period 2004 – 2013 were diagnosed after delivery, having had infants exposed to HIV and not having access to the established antenatal strategies to prevent mother-to-child transmission (Table 1).[1] Some women with HIV may have an unintended pregnancy; only a few will decide to terminate their pregnancy, often for reasons not directly related to HIV infection.

Table 1 Number of perinatally exposed children born in Australia, 2004-2013, and number with diagnosed HIV infection by year of the child’s birth and time of woman’s diagnosis relative to the child’s birth[2]

Child’s year of birth

Before or at the birth

After the birth

Total

 

Number exposed

Number with HIV

Number exposed

Number with HIV

Number exposed

Number with HIV

2004-2005

45

0

4

2

50

2

2006-2007

52

3

5

3

57

6

2008-2009

76

0

0

0

79

1

2010-2011

85

1

2

0

88

1

2012-2013

99

1

3

2

108

3

Total

357

5

14

7

382

13

Source: The Kirby Institute. HIV, viral hepatitis and sexually transmissible infections in Australia. Annual Surveillance Report 2014.  Sydney; The Kirby Institute, UNSW: 2014.

Women with HIV will each have different journeys which may include one or more pregnancies. Providing ongoing care and support to all women who do embark upon a pregnancy, and providing care to their infants after delivery, remain challenging, but extremely rewarding experiences we all face as HIV clinicians.

HIV testing in pregnancy – a priority

The National HIV Testing Policy recommends that all pregnant women should be routinely offered HIV testing, which should be performed with consent, preferably at the first antenatal visit.[3] The risk of perinatal transmission of HIV can be significantly reduced by a number of established evidence-based antenatal and postnatal interventions and appropriate care throughout the pregnancy. Pregnancy is an opportune time for women to be tested when they present to clinicians; the consultation allows for the detection of previously undiagnosed infections, especially in a low prevalence country like Australia. Testing women in pregnancy is a high priority.

Previous policy had suggested that HIV testing in pregnancy be undertaken based on a risk assessment. However for most women, the only identifiable risk may be heterosexual exposure with a very limited number of lifetime sexual partners. Therefore the standard risk assessment may not be adequate to test and detect all women with HIV infection. Because prevention of mother-to-child transmission of HIV is highly effective if HIV is diagnosed antenatally, routine testing with informed consent is now the standard of care offered to all women in pregnancy. In addition, it is important to offer all women with newly diagnosed HIV infection a sexual health screen.

A diagnosis of HIV in pregnancy can result in considerable anxiety and often guilt for any woman with HIV infection. It will also necessitate testing of the women’s sexual partners. Disclosure to a sexual partner may increase the woman’s anxiety considerably. Some woman may be particularly vulnerable, have fears of rejection or be at significant risk, particularly if they are in a relationship that involves domestic violence. Therefore special psychosocial support should be offered to all women diagnosed with HIV in pregnancy.

Conception counselling

Routine reproductive counselling is essential for all women with HIV.[4] In a survey in 2011 of 700 women with HIV infection, 22% of whom became pregnant after an HIV diagnosis, 58% had never discussed pregnancy or treatment options before pregnancy and 42% had limited or no knowledge of antiretroviral  options.[5]

Health providers seeing women with HIV infection should initiate a non-judgmental conversation with all women of child-bearing age concerning their reproductive desires. This process is ongoing but should be initiated in an appropriate timely manner shortly after initial HIV diagnosis.

Many women are aware of their HIV status before becoming pregnant and therefore issues that affect contraception and pregnancy can be addressed during their routine visits for HIV care. Of course not all women with HIV infection will desire to become pregnant and they may have contraceptive needs that should be addressed. Some women with HIV may be reluctant to initiate this discussion.  Health-care providers play an important role in optimising preconception health and supporting women to make informed reproductive decisions.

Preconception counselling and care should be offered to all women with HIV infection and ideally should:

  • be incorporated into routine health visits
  • facilitate comprehensive family planning
  • allow a woman’s reproductive wishes to be re-visited over time during her reproductive years, as relationships and circumstances may change
  • provide education and counselling targeted to the woman’s individual needs (does she want to achieve a pregnancy or avoid an unintended pregnancy)
  • allow ongoing identification of all potential risk factors for adverse maternal or fetal outcomes (e.g. increasing maternal age)
  • address all health issues and allow for the woman’s health to be optimised (Table 2).

Table 2 Preconception checklist
 

•      Assess safer sexual practices and contraceptive methods (including condoms)

•      Recommend balanced diet and specific dietary advice

•      Check vaccination status (influenza, pneumococcal)

•      Check serology – hepatitis C virus (HCV), hepatitis B virus (HBV), varicella zoster virus (VZV), measles, mumps, rubella (MMR), syphilis

•      Include (but not limited to) blood group, iron (Fe) studies

•      Assess tuberculosis (TB) exposure risk if not previously undertaken

•      Prescribe folic acid 1-5 mg/day before  conception and during first trimester

•      Screen for sexually transmissible infections (STI) including syphilis serology and provide treatment as required

•      Perform pelvic exam, Pap smear

•      Address substance use (alcohol, illicit drugs, smoking)

•      Optimise mental and physical health before pregnancy

•      Discuss reproductive options including strategies for serodiscordant couples

•      Discuss perinatal transmission risks and prevention of mother-to-child transmission strategies including avoidance of breastfeeding

•      Refer to infertility services when required

•      Encourage sexual partners to have an HIV test, counselling and to engage in care.


Contraception

Recent studies have indicated that one in five women with HIV is not using any contraceptive method, a rate which is higher than in the general population. High rates of unintended pregnancies have been reported in some settings with proportions ranging from 50-85%, with condoms being the most commonly used contraceptive method.[6]

It is important to offer all women with HIV who do not desire a pregnancy, effective and appropriate methods to reduce the risk of an unintended pregnancy. Women with HIV infection can use all available contraceptive methods, including hormonal contraception, emergency contraception and long-acting reversible contraceptives (LARCs). The method of contraception to be used should be chosen in discussion with the woman, and should be acceptable and medically appropriate with consideration of cardiovascular, thrombotic and stroke risk, together with aura with worsening migraine or worsening migraine on combination hormonal contraceptives.[7]

A World Health Organization expert panel has reviewed all available evidence regarding hormonal contraception and the potential effect on HIV transmission to a partner without infection and has recommended that women with HIV infection can use all available hormonal contraceptive methods without restriction.[8] 

Many antiretroviral drugs have inducing or inhibiting effects on the cytochrome P450 system and as hormonal contraceptives are metabolised by cytochrome P450 isoenzymes there are significant drug-drug interactions between hormonal contraceptives and combination antiretroviral therapy (cART) which may lead to contraceptive failure.[9] Detailed interactions are available in existing antiretroviral guidelines.[10] A practical guide is summarised below (Table 3).  It should be noted that data on drug-drug interactions between antiretroviral drugs and hormonal contraceptives are primarily derived from drug labels and limited studies and the clinical significance has not been well studied.  The magnitude of change in contraceptive efficacy may not be well known in all instances.

 

 Table 3 Contraception and antiretroviral drug interactions - a brief summary of the guidelines.[11]

Antiretroviral agent

Combined oral contraceptive pill

Progestogen-only pill

Contraceptive implant (Implanon NXT)

Contraceptive injection DMPA (Depo-Provera and Depo-Ralovera)

Intrauterine contraceptive device (Mirena)

Zidovudine, tenofovir, abacavir, lamivudine /emtricitabine

R

R

R

R*

R

Efavirenz, nevirapine

NR

NR

NR

R**

R

 

Rilpivirine

R

R

R

R

R

 

Raltegravir

R

R

R

R

R

 

Dolutegravir

R

R

R

R

R

 

Maraviroc

R

R

R

R

R

 

Atazanavir

Atazanavir/ ritonavir

OK with < 30 µg EE+**

OK with >35 µg EE+**

NR

NR

NR

R

 

 

Darunavir/ ritonavir , lopinavir, tipranavir / ritonavir , fosamprenavir / ritonavir

NR

NR

NR

R

R

 

 

 

Elvitegravir + cobicistat

NR

NR

NR

R

R

 

 

R: Recommended without additional contraceptive protection
 NR: Not recommended – use alternative or additional contraceptive method 

*DMPA (depot medroxyprogesterone acetate) with tenofovir – concerns that both may decrease in bone density
+Oral contraceptives containing progestogens other than norethindrone or norgestimate have not been studied
**<25 µg ethinyl oestradiol (EE) have not been studied

 
Prevention of mother-to-child transmission

The first major study in HIV prevention in pregnancy was the Paediatric AIDS Clinical Trials PACTG 076 in 1994. This placebo controlled study demonstrated that the administration of zidovudine to pregnant women and their infants could reduce the risk of perinatal transmission by 67.5% overall.[12] [13]  More recent studies have explored the efficacy of shorter, less expensive antiretroviral regimens usually more applicable to resource-limited settings and have also examined regimens to reduce postnatal transmission during labour and breastfeeding.

A number of effective strategies have now been established to prevent mother-to-child transmission during pregnancy, at the time of labour and delivery and in the postnatal period. With the implementation of recommendations for universal prenatal HIV counselling and testing, antiretroviral (ARV) prophylaxis, scheduled caesarean delivery when indicated, and avoidance of breastfeeding, the rate of perinatal transmission of HIV has dramatically diminished to 2% or less in the United States of America, Europe and Australia.28 In the developed world, the goal of HIV treatment in pregnancy is now to achieve a transmission risk  less than 1%.[14] [15] [16] [17] A number of factors have been identified that may affect the risk of perinatal transmission. The most significant risk factor for transmission is the maternal plasma HIV viral load. Different risks are evident during different times of the pregnancy with labour and delivery being the period of greatest risk for the infant.

There are many factors that may affect perinatal transmission:

Viral

  • Viral load (cell associated/cell free)
  • Phenotype (syncytium-inducing (SI), tropism)
  • Genotype

Immunological

  • Decreased CD4 count
  • Humoral (NAb, ADCC/ gp120 V3 loop Ab, other)
  • Cell mediated (CTL, CD8 suppression)
  • Mucosal immunity

Maternal

  • Clinically advanced disease – low maternal CD4 count
  • Primary HIV infection
  • Co-infection with hepatitis C virus (HCV)
  • Twins - first born

Obstetric events [18]

  • Duration of labour with rupture of membranes (ROM) more than 4 hours in the absence of full virological suppression[19] [20]
  • Timing of infection
  • Antiretroviral use in pregnancy[21]
  • Mode of delivery – benefit of caesarean section in the absence of full virological suppression[22] [23] [24] [25]
  • Breastfeeding (approximately an additional 30% risk postpartum)[26] [27] [28] [29] [30]
  • Mixed feeding (increased risk over exclusive breastfeeding)
  • Some interventions e.g. fetal blood sampling, scalp electrodes

Fetal/placental

  • Prematurity
  • Chorioamnionitis
  • Infant host-immune response.

Significant advances have been made in the prevention of mother-to-child transmission. The proven strategies for prevention are:

Combination antiretroviral therapy (cART)

    • cART for the mother
    • For the baby – antiretroviral post-exposure prophylaxis (PEP). For mothers with viral load below 50 copies/mL and prevention of mother-to-child transmission strategies in place, zidovudine monotherapy for 4 weeks is recommended. It is a more complex situation where the risk of mother-to-child transmission is higher e.g. where mothers have not received antenatal antiretroviral therapy, and additional antiretroviral therapy for the baby will be decided upon by the paediatric team[31]
    • In addition, intravenous (IV) zidovudine may be used during delivery if it is a late diagnosis, or the viral load is more than 400 copies/mL.[32] [33]

Mode of delivery[34] [35] [36]

  • The role of caesarean section delivery has changed over time. If maternal viral load is undetectable, (below 50 copies/mL with the women being on treatment for more than 4 weeks), there is no evidence of additional benefit from a planned caesarean delivery and many women are now having a vaginal delivery.[37]
  • If delivery by caesarean section is planned it should be undertaken at 38 weeks gestation.
  • Avoidance of invasive measures at the time of labour and delivery e.g. scalp electrodes. The use of forceps and ventouse extraction may potentially increase the risk of transmission but this does not preclude their use if required.

Avoidance of breastfeeding[38] [39] [40] [41] [42].

  • The many benefits of breastfeeding are acknowledged. However avoidance of breastfeeding is recommended for all mothers in Australia even when they are on cART as there is still a risk of transmission of 2 - 5%.[43] [44] Breastfeeding (exclusive) is still recommended in resource-limited settings without access to a clean water supply.[45]

Principles of antiretroviral use in pregnancy

Antiretroviral drugs for prevention of perinatal transmission of HIV are recommended for all pregnant women, regardless of CD4 cell counts and HIV RNA levels, and will reduce perinatal transmission through a number of mechanisms. Antenatal drug administration decreases maternal viral load in blood and genital secretions. A number of studies have shown that the penetration of ARV drugs into the female genital tract has been shown to vary between drugs.

Initiation of antiretroviral therapy

If HIV is first diagnosed in pregnancy consideration should be given to initiating cART as soon as possible. However, after discussion, some women may elect to commence treatment after the first trimester (providing it does not disadvantage her care). 

The goal is to safely reduce the viral load to undetectable well before and during delivery regardless of maternal stage of disease [46] or baseline viral load, and also to ensure that the mother herself will receive effective cART throughout pregnancy (and beyond).  Discontinuation of antiretroviral therapy during pregnancy should be avoided as an increase in viral load will result in an increased risk of transmission to the fetus and possible decline in immune status of the mother.[47]

The use of antiretroviral therapy is highly effective, even in women with advanced disease. Note that pregnancy does not accelerate HIV disease progression (unless the mother already has advanced disease or acquired immune deficiency syndrome [AIDS]).

cART regimens are more effective than single-dose regimens in reducing mother-to-child transmission, and are the standard of care. Longer duration of treatment and earlier initiation of antiretroviral therapy is more effective than shorter duration and later initiation as earlier full viral suppression will lower the risk of transmission for the fetus.[48] Ideally cART should be commenced before 28 weeks gestation. 

All antiretroviral-naïve women should have a baseline HIV genotype resistance assay performed. This assay should be performed for any woman with virological failure during pregnancy requiring a treatment modification, viral load permitting (greater than 1000 copies/mL).

Choice of antiretroviral agents[49] [50]

In general, the same regimens as recommended for treatment of non-pregnant adults with HIV infection should be used in pregnant women, with special consideration of existing safety data. However, drug treatment must always be individualised. Consult current guidelines regarding current recommendations.[51]

For women already on treatment, continuation of cART is recommended. There may be concerns about limited experience or limited safety data with newer agents in regard to drug toxicity and teratogenicity and consideration must always be given to known adverse effects for the woman, fetus or infant that outweigh the benefits. 

The goals and issues for consideration are the same as in non-pregnant women: potency, durability, preservation of future options, toxicity and tolerability, resistance and, particularly, adherence throughout the whole pregnancy.[52] [53] The need for strict adherence to prescribed medication throughout the pregnancy should be re-inforced and factors that may adversely affect adherence should be identified and addressed. Treatment modifications during pregnancy should be avoided unless absolutely necessary. Treatment changes undertaken in pregnancy are associated with increased risk of incomplete viral suppression at the end of pregnancy.[54]

It is now recommended that all women continue cART following the delivery of their infant. However several studies have shown that the mother’s adherence to cART may deteriorate in the postpartum period.[55] Viral load monitoring has been shown to be valuable in enhancing adherence.[56]

Recommendations for the use of antiretroviral agents in pregnancy

Current recommendations for specific antiretroviral agents are available in existing guidelines (USA and UK).[57] [58]

Preferred antiretroviral drugs are those agents with clinical trial data in adults that have demonstrated:

  • optimal efficacy and durability
  • acceptable toxicity and ease of use
  • pregnancy-specific PK data available to guide dosing
  • no associated teratogenic affects
  • no reported maternal, fetal or newborn adverse outcomes.

Transplacental passage of antiretroviral agents is an important mechanism of infant pre-exposure prophylaxis (PrEP). For this reason at least one nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) with a high placental transfer should be included in the cART regimen.

The US guidelines currently recommend a cART regimen in pregnancy consisting of two NRTIs and a ritonavir-boosted protease inhibitor (PI/r) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) or an integrase inhibitor.

Table 4 is a direct summary of the current recommendations in the USA for antiretroviral-naive pregnant women. Refer to the full guidelines for the rationale for drug selection.[59]

Table 4.  Initial combination regimens for antiretroviral-naive pregnant women.[60]  (http://aidsinfo.nih.gov/guidelines, Table 6 pg c-30)

 

A. Drugs that are approved for use in adults but lack adequate pregnancy-specific PK or safety data:

DRUG

COMMENTS

DTG

No data on use of DTG in pregnancy.

EVG/COBI/TDF/FTC

No data on use of EVG/COBI component in pregnancy.

FPV

Limited data on use in pregnancy.

MVC

Requires tropism testing before use. Few case reports of use in pregnancy.

COBI

No data on use of COBI (including coformulations with ATV or DRV) in pregnancy.Not Recommended: Drugs whose use is not recommended because of toxicity, lower rate of viral suppression or not recommended in antiretroviral therapy-naive women:

 

B. Not Recommended: Drugs whose use is not recommended because of toxicity, lower rate of viral suppression or not recommended in antiretroviral therapy-naive women:

ABC/3TC/ZDV

Generally not recommended due to inferior virological efficacy

D4T, ddI

Not recommended due to toxicity

IDV/r

Nephrolithiasis, maternal hyperbilirubinaemia

NFV

Lower rate of viral suppression with NFV compared to LPV/r or EFV in adult trials

RTV

RTV as a single PI is not recommended because of inferior efficacy and increased toxicity

SQV/r

Not recommended based on potential toxicity and dosing disadvantages. Baseline ECG is recommended before initiation of SQV/r because of potential PR and QT prolongation; contraindicated with pre-existing cardiac conduction system disease. Limited data in pregnancy. Large pill burden. Twice daily dosing required

ETR

Not recommended in ART-naive populations.

NVP

Not recommended because of greater potential for adverse events e.g. hypersensitivity reaction, and complex lead-in dosing, and low barrier to resistance. NVP should be used with caution when initiating ART in women with CD4 cell count >250 cells/mm3.

T20

Not recommended in ART-naive populations.

TPV/r

Not recommended in ART-naive populations

 

C. Preferred regimens
Regimens with clinical trial data in adults demonstrating optimal efficacy and durability with acceptable toxicity and ease of use, PK data available in pregnancy, and no evidence to date of teratogenic effects or established adverse outcomes for mother, fetus and newborn.

Preferred two-NRTI backbone

ABC/3TC (HLAB5701 negative); TDF/FTC or 3TC; ZDV/3TC

Preferred PI regimens

ATV/r plus a preferred two-NRTI backbone - once-daily administration. Extensive experience in pregnancy. Maternal hyperbilirubinemia;

DRV/r plus a preferred two-NRTI backbone - better tolerated than LPV/r. PK data available. Increasing experience with use in pregnancy. Must be used twice daily in pregnancy.

Preferred NNRTI regimen:

EFV plus a preferred two-NRTI backbone
Note: May be initiated after the first 8 weeks of pregnancy (compare to BHIVA Guidelines).

Preferred Integrase Inhibitor regimen

RAL plus a preferred two-NRTI backbone:  PK data available and increasing experience in pregnancy. Rapid viral load reduction.  Useful when drug interactions with PI regimens are a concern. Twice-daily dosing required.

Key to Acronyms: 3TC = lamivudine; ABC = abacavir; ART = antiretroviral therapy; ARV = antiretroviral; ATV/r = atazanavir/ritonavir; CD4 = CD4 T lymphocyte cell; COBI = cobicistat; d4T = stavudine; ddI = didanosine; DTG = dolutegravir; DRV/r = darunavir/ritonavir; ECG = electrocardiogram; EFV = efavirenz; ETR = etravirine; EVG = elvitegravir; FDC = fixed-dose combination; FPV = fosamprenavir; FTC = emtricitabine; IDV/r = indinavir/ritonavir; LPV/r = lopinavir/ritonavir; MVC = maraviroc; NFV = nelfinavir; NRTI = nucleoside reverse transcriptase inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; NVP = nevirapine; PI = protease inhibitor; PPI = proton pump inhibitor; PK = pharmacokinetic; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; SQV/r = saquinavir/ritonavir; T20 = enfuvirtide; TDF = tenofovir disoproxil fumarate; TPV = tipranavir; ZDV = zidovudine

Special issues in pregnancy

Some pregnancy specific issues will need special consideration e.g. demonstrated efficacy of  antiretroviral drugs in prevention of mother-to-child transmission, maternal and fetal toxicity, teratogenicity, PK studies, resistance testing before and during pregnancy, transplacental transfer, timing of treatment initiation, hyperemesis and nausea of pregnancy.  Sometimes if the mother is experiencing severe hyperemesis, cART may need to be ceased temporarily.  All medication usually will need to be stopped simultaneously and re-introduced simultaneously as soon as possible, accepting the potential problem that might arise with drugs with long half-lives (e.g. nevirapine and efavirenz). 

PK changes in pregnancy may lead to lower plasma levels of some drugs and necessitate increased dosages, more frequent dosing or boosting e.g. boosted lopinavir (commonly used in the past in pregnancy) require an increased dose in the third trimester to three tablets twice daily. PK studies are continuing for the newer antiretroviral agents. For example, recent studies of once daily ritonavir-boosted darunavir (DRV/r 800/100 mg) indicated that this regime provided adequate exposure to achieve viral suppression and was safe and well tolerated.[61] However plasma concentrations postpartum were higher than in the second and third trimester, so assessment of adherence is important, as are any concomitant medications that may further decrease DRV levels. DRV/r twice daily has previously been shown to be a treatment option for women with HIV infection with or without DRV resistance-associated mutations. Further PK studies of etravirine 200 mg twice daily indicated higher levels in the second and third trimester than postpartum but this was not considered clinically relevant.[62] Further studies are ongoing in this area.

Drug safety in pregnancy

Information regarding the safety of drugs in pregnancy is derived from animal toxicity data, anecdotal experience, registry data, observational cohorts and clinical trials.  Preclinical data includes results of in vitro and animal in vivo screening tests for carcinogenicity, reproductive and teratogenic effects.  However the predictive value of such tests in humans is unknown.  Ultimately it could be argued that the choice of antiretroviral therapy in pregnancy has often been based on collective experience, accumulated safety data over time and consensus guidelines, rather than on randomised trials.

Teratogenicity of antiretroviral drugs

There is no increased risk of congenital abnormalities in infants born to mothers with HIV infection (Table 5).  Reports of birth defects in fetuses and infants of women enrolled in observational studies are reassuring with no difference in rates of birth defects for the first trimester compared with later exposures being observed.  The known benefits and potential unknown risks of antiretroviral drug use during pregnancy (including limited long-term outcome data for infants with in utero drug exposure) should be discussed with the mother.[63] The need for strict adherence to prescribed medication throughout the pregnancy should always be reinforced. 

Health-care providers caring for women with HIV infection and their infants with prenatal exposure are encouraged to report de-identified, observational, non-experimental pregnancy outcome data to the Antiretroviral Pregnancy Registry.  The purpose of the Antiretroviral Pregnancy Registry  is to detect any major teratogenic effects of the antiretroviral drugs to which pregnant women are exposed. Although the Registry is international, reports are predominantly from the USA (77.3%). Rates of reported defects are compared with rates from two external comparator populations, the Metropolitan Atlanta Congenital Defects Program (MACDP) and the Texas Birth Defects Registry (TBDR).

Table 5.  Interim Report from the Antiretroviral Pregnancy Registry, Volume 28, Number 1. 1 January 1989 through 31 January 2016 (Issued: June 2016) (Expiration 6 months after issue)[64]

A summary of defects  per live births with first trimester exposure as at January 2016 are as follows:

Antiretroviral

Defects/live births

Prevalence (95% Confidence Interval)

Lamivudine

143/4589

3.1% (2.6%,3.7%)

Zidovudine

133/4128

3.2% (2.7%, 3.8%)

Stavudine

20/422

4.7% (2.9%, 7.2%)

Indinavir

7/289

2.4% (1.0%, 4.9%)

Ritonavir

64/2815

2.3% (1.7%, 2.9%)

Nelfinavir

47/1213

3.9% (2.9%, 5.1%)

Tenofovir (TDF)

61/2779

2.2% (1.7%, 2.8%)

Nevirapine

32/1113

2.9% (2.0%, 4.0%)

Lopinavir

29/1290

2.2% (1.5%, 3.2 %)

Atazanavir

24/1142

2.1% (1.3%, 3.1%)

Abacavir

30/1067

3.0% (2.0%, 4.2%)

Emtricitabine

48/2145

2.2% (1.6%.3.0%)

Efavirenz

22/902

2.4% (1.5%, 3.7%)

Darunavir

10/352

2.8% (1.4%, 5.2%)

Raltegravir

6/201

3.0% (1.1%, 6.4%)

Source: The Antiretroviral Pregnancy Registry. Available at: http://www.APRegistry.com

Specific drugs safety issues in pregnancy

Efavirenz

Efavirenz has long been classified as a Category D drug in pregnancy (for definitions of Australian categorisation system for prescribing medicines in pregnancy, see https://www.tga.gov.au/australian-categorisation-system-prescribing-medicines-pregnancy) following the initial reports of the preclinical primate data and retrospective reports in humans of increased risk of neural tube defects. However a recent meta-analysis of 1437 women in 19 studies with first trimester efavirenz exposure found no increased risk of birth defects and only one neural tube defect (incidence: 0.07%).[65]

Current British HIV Association (BHIVA) guidelines 2014 recommend that effective efavirenz -based antiretroviral therapy be continued in a woman presenting in the first trimester. The US guidelines in contrast recommend initiating cART after the first 8 weeks of pregnancy.

Pregnancy recognition often occurs after the critical time of organogenesis and the development and closure of the neural tube is usually complete by 28 days postconception. Therefore, in theory, changes to efavirenz-based regimens after 4 weeks postconception will not significantly reduce the risk of neural tube defects and after 8 weeks will have minimal effect on the risk for other structural defects in regard to efavirenz exposure.

Atazanavir

Atazanavir is associated with an increased indirect bilirubin level in the mother which in theory might increase the risk of hyperbilirubinaemia in the neonate.  A number of studies have shown no pathologic elevations of concern to date.[66]

Tenofovir

There have been some concerns in regard to bone and growth abnormalities in infants exposed to tenofovir in utero.  However the duration of treatment and clinical significance of any study findings still require further evaluation and the findings thus far do not preclude the use of tenofovir in pregnancy.

Preterm delivery

Early and more recent data are conflicting in regard to whether cART during pregnancy is associated with adverse pregnancy outcomes, specifically with preterm delivery (before 37 weeks). Multiple observational studies have detected small but significant increases in preterm birth with PI-based and non PI-based cART.[67] [68] Conflicting findings may be influenced by a number of factors, e.g. data variability available for analysis, the time when antiretroviral agents were commenced, HIV disease severity (an independent factor), maternal age and intravenous drug use.

These findings should not prevent the current agents from being used as the benefits of effective agents in pregnancy currently outweigh concern for any increased risk of preterm delivery.

Monitoring of women during pregnancy

Viral load

More frequent viral load monitoring in pregnant women with HIV infection is recommended to ensure rapid and sustained virological suppression has been achieved.  Viral load should be assessed at the initial visit, 2 - 4 weeks after initiating or changing antiretroviral regimens, monthly until undetectable and at least 3 monthly thereafter.  If adherence is a concern, more frequent monitoring is required.

Viral load should also be assessed at 34 - 36 weeks gestation to inform decisions about the mode of delivery and optimal treatment of the newborn.

CD4 cell count

In women with HIV infection CD4 cell counts can be performed at the initial visit, and at least 3 monthly during pregnancy in women with newly initiated treatment.  CD4 cell counts can be performed every 6 months in women who are clinically stable with long-term full virological suppression and a CD4 cell count well above the threshold for risk of any opportunistic infection.  Note that the CD4 cell count will often go down slightly during pregnancy but will return to pre-pregnancy levels after delivery.

Other monitoring issues

Pregnancy increases the risk of hyperglycaemia and women will usually have an oral glucose tolerance test performed during pregnancy, usually at 24 - 28 weeks gestation.  The majority of studies in women with HIV infection have not shown an increased risk of glucose intolerance and insulin resistance in women on PI-based regimens in pregnancy.[69]

First trimester ultrasound is recommended to confirm the exact gestational age and inform future planning for delivery, particularly for women choosing to have a caesarean section delivery at 38 weeks gestation. Further ultrasound examinations will also usually be performed during the pregnancy at 19 and 34 weeks gestation.

Paediatric referral

It is vital to involve a paediatric multidisciplinary team before the birth of the infant.  The team, consisting of a paediatrician, nursing staff, social worker and dietitian, will support the mother and family in many ways, including the following:

  • counselling and support of the mother and her partner during pregnancy and after delivery of the baby
  • providing information on the strategies to prevent mother-to-child transmission
  • providing an outline of the necessary testing schedule of the infant, up to 18 months of age, and the tests to be undertaken - HIV antibody, together with HIV DNA (proviral) PCR or HIV RNA PCR[70] [71]
  • providing information and support regarding antiretroviral medication for the baby after birth and the recommendation regarding not breastfeeding. Not being able to breastfeed can be very confronting for many mothers in many cultures, and support by the paediatric team is invaluable in assisting with this issue
  • providing information regarding vaccination after birth. Routine vaccinations should be given to all babies according to the Australian Immunisation Schedule
  • developing a Care Plan of antenatal and postnatal management, always in consultation with the mother, to assist all health providers involved in care – HIV physician, obstetrician, general practitioner, and the delivery suite
  • providing ongoing care and support to the infants who are newly diagnosed with HIV infection. Paediatric care and support will continue into adolescence and will include, but not be limited to, Camp Goodtime and preparing the way for children to negotiate school commencement confidentially.

Reproductive options for HIV seroconcordant and serodiscordant couples


More and more HIV consultations around pregnancy issues are involving serodiscordant couples, and on occasions, seroconcordant couples.  For these couples referral for expert consultation is recommended.

In brief, recent studies have provided evidence of the effectiveness of cART in preventing sexual transmission, i.e. treatment as prevention. (HPTN 052 and Partner Study).[72] [73] However cART may not eliminate sexual transmission risk in all couples who have decided to conceive through unprotected intercourse.  Further studies will continue to add to our current knowledge in this area.

Reproductive health needs of seroconcordant and serodiscordant couples can, very briefly, be outlined as follows:[74]

  • For couples in which both partners have HIV infection (although rarely, they might have different genotypes), both partners should have attained optimal health before conception.  They should have demonstrated sustained full virological suppression before attempting a pregnancy through unprotected intercourse.
  • For serodiscordant couples[75] where the female partner has HIV infection and is on cART, the safest form of conception is (home) artificial vaginal insemination during the time of ovulation (and condom use at other times).
  • For serodiscordant couples where the male partner has HIV infection, they should both be on cART and have demonstrated sustained full virological suppression for at least 6 months.[76] Unprotected intercourse should be limited to the time of ovulation.  The availability or peri-conception PrEP (pre-exposure prophylaxis) for the HIV-negative partner is now a possibility.[77] [78]  If this is used, PrEP should be continued for at least 1 month after conception is achieved and revisited throughout the pregnancy if there is any ongoing risk of seroconversion during pregnancy.

 

For this couple the alternative safest option is donor sperm and in the past, sperm washing (which had extremely limited availability) followed by artificial insemination or in vitro fertilisation (IVF) or  Intracytoplasmic sperm injection (ICSI).

  • Access to assisted reproductive technology (including IVF/ICSI) should be accessible for all couples as required to address infertility issues.

 

Conclusion

The future models of care for couples with HIV infection will encompass integrated HIV, obstetric and paediatric care, contraception when required, and integrated care for couples, which will include early access to treatment as prevention and PrEP access for serodiscordant couples.  

 

Case Study 1

Agnes is a 28-year-old woman from Zimbabwe.  She arrived in Australia 6 months ago and has no family supports.  She is diagnosed as having HIV infection and she is also 10 weeks pregnant.  She is non-Medicare eligible at this time.  Initial investigations indicate a CD4 count of 190 cells/μL and a HIV RNA viral load of 43 000 copies/mL.
What are the key issues for this young woman that need to be considered and the possible solutions that are available? 

 

Case Study 2

Samuel was diagnosed as having HIV infection in 2005. He has been in a relationship with Sue for the past 7 years and they are now very keen to have a child. Sue has been engaged in long-term counselling regarding severe anxiety, including ongoing anxiety about acquiring HIV.  Samuel is currently on truvada and raltegravir and his viral load has been undetectable for the past 10 years.

What are the key issues for this couple and the available solutions?

 

Key points
  • Antiretroviral therapy in pregnancy is the standard of care and is commenced regardless of baseline CD4 count, viral load or stage of disease
  • When all recommended strategies are implemented, the mother-to-child transmission risk is now considered to be below 2% in developed world settings
  • Treatment should be commenced as soon as possible if the woman is not already on therapy (but some women may prefer to wait until after the first trimester if antiretroviral naive)
  • Choice of specific antiretroviral drug relates to demonstrated efficacy and safety
  • cART is continued after delivery
  • Refer to guidelines and colleagues experienced in the management of both HIV and pregnancy
  • Women with HIV infection require more frequent monitoring during pregnancy
  • Management of pregnant woman with HIV infection requires a coordinated team approach - HIV physician, obstetrician, paediatric HIV specialist for the baby, midwives and allied health staff. 

 

Resources

http://www.APRegistry.com
Antiretroviral Pregnancy Register maintains an up-to-date registry of antiretroviral drug exposure during pregnancy.

http://aidsinfo.nih.gov/guidelines
Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States.

Family Planning NSW: Contraception: an Australian clinical practice handbook. 4th edition; 2016. 

MotherSafe http://www.mothersafe.org.au
Counselling service for health providers and mothers regarding concerns about perinatal exposure.

WHO 2010 http://www.who.int/hiv/pub/mtct/PMTCTfactsheet/en/
WHO guidelines on prevention of mother-to-child transmission and breastfeeding.

http://ww.hiv-druginteractions.org
University of Liverpool HIV Drug Interactions website.

1.
The Kirby Institute. HIV, viral hepatitis and sexually transmissible infections in Australia. Annual Surveillance Report 2014.  Sydney; The Kirby Institute, UNSW: 2014. 
2.
The Kirby Institute. HIV, viral hepatitis and sexually transmissible infections in Australia. Annual Surveillance Report 2014.  Sydney; The Kirby Institute, UNSW: 2014. 
3.
2014 National HIV Testing Policy. v1.0. Available at: http://testingportal.ashm.org.au/resources/2014_National_HIV_Testing_Policy_v1.pdf (last accessed 10 August 2016). 
4.
Hoyt MJ, Storm DS.Aaron E, Anderson J. Preconception and contraceptive care for women living with HIV. Infect Dis Obstet Gynecol 2012;2012:604183. 
5.
Squires KE, Hodder SL, Feinberg J, et al. Health needs of HIV-infected women in the United States: insights from the women living positive survey. AIDS Patient Care STDS 2011;25:279-85. 
6.
Mitchell HS, Stephens E. Contraceptive choice for HIV positive women. Sex Transm Infect 2004;80:167-73. 
7.
Bateson D, McNamee K, O’Connor V. Contraception: an Australian clinical practice handbook. 4th edition. Sydney: Family Planning New South Wales (FPNSW), Family Planning Queensland (FPQ), Family Planning Victoria (FPV); 2016. 
8.
Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention (CDC). US Selected Practice Recommendations for Contraceptive Use, 2013: adapted from the World Health Organization Selected Practice Recommendations for Contaceptive Use. 2nd edition. MMWR Recomm Rep 2013;62 (RR05):1-60. 
9.
Robinson JA, Jamshidi R, Burke AE. Contraception for the HIV-positive woman: a review of interactions between hormonal contraception and antiretroviral therapy. Infect Dis Obstset Gynecol 2012;2012:890160. 
10.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. (Last updated: August 6, 2015; last reviewed: August 6, 2015) Access via: http://aidsinfo.nih.gov/guidelines
11.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. (Last updated: August 6, 2015; last reviewed: August 6, 2015) Access via: http://aidsinfo.nih.gov/guidelines
12.
Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med 1994;331:1173-80. 
13.
Centers for Disease Control and Prevention (CDC). Zidovudine for the prevention of HIV from mother to infacnt. MMWR Morb Mortal Wkly Rep 1994;43:285-7. 
14.
Townsend CL, Cortina-Borja M, Peckham CS, de Ruiter A, Lyall H, Tookey PA. Low rates of mother-to-child transmission of HIV following effective pregnancy interventions in the United Kingdom and Ireland, 2000-2006. AIDS 2008;22:973-81. 
15.
Centers for Disease Control and Prevention. (CDC). Enhanced perinatal surveillance—15 areas, 2005–2008. HIV Surveillance Supplemental Report 2011. 2011;16:2011. Available at: http://www.cdc.gov/hiv/pdf/statistics_2005_2008_HIV_Surveillance_Report_vol_16_no2.pdf (last accessed 3 March 2016). 
16.
Whitmore SK, Taylor AW, Espinoza L, Shouse RL, Lampe MA, Nesheim S. Correlates of mother-to-child transmission of HIV in the United States and Puerto Rico. Pediatrics 2012;129:2010-3691. 
17.
Centers for Disease Control and Prevention (CDC). Achievements in public health. Reduction in perinatal transmission of HIV infection--United States, 1985-2005. MMWR Morb Mortal Wkly Rep 2006;55:592-7 
18.
Landesman SH, Kalish LA, Burns DN, et al. Obstetrical factors and the transmission of human immunodeficiency virus type 1 from mother to child. The Women and Infants Transmission Study. N Engl J Med 1996;334:1617-23. 
19.
International Perinatal HIV Group. Duration of ruptured membranes and vertical transmission of HIV-1: a meta-analysis from 15 prospective cohort studies. AIDS 2001;15:357-68. 
20.
Peters H, Byrne L, De Ruiter A, et al. Duration of ruptured membranes and mother-to-child HIV transmission: a prospective population-based surveillance study. BJOG 2015. 
21.
Nielsen-Saines K, Watts DH, Veloso VG, et al. Three postpartum antiretroviral regimens to prevent intrapartum HIV infection. N Engl J Med 2012;366:2368-79. 
22.
Read JS, Newell MK. Efficacy and safety of cesarean delivery for prevention of mother-to-child transmission of HIV-1. Cochrane Database Syst Rev 2005; (4):CD005479. 
23.
The International Perinatal HIV Group. The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1--a meta-analysis of 15 prospective cohort studies. N Engl J Med 1999;340:977-87. 
24.
Briand N, Jasseron C, Sibiude J, et al. Cesarean section for HIV-infected women in the combination antiretroviral therapies era, 2000-2010. Am J Obstet Gynecol 2013;209(4):335.e1-335.e12. 
25.
Dahlke JD, Mendez-Figueroa H, Rouse DJ, Berghella V, Baxter JK, Chauhan SP. Evidence-based surgery for cesarean delivery: an updated systematic review. Am J Obstet Gynecol 2013;209:294-306. 
26.
Nduati R, John G, Mbori-Ngacha D, et al. Effect of breastfeeding and formula feeding on transmission of HIV-1: a randomized clinical trial. Jama 2000;283:1167-74. 
27.
Coovadia HM, Rollins NC, Bland RM, et al. Mother-to-child transmission of HIV-1 infection during exclusive breastfeeding in the first 6 months of life: an intervention cohort study. Lancet 2007;369:1107-16. 
28.
Thomas TK, Masaba R, Borkowf CB, et al. Triple-antiretroviral prophylaxis to prevent mother-to-child HIV transmission through breastfeeding--the Kisumu Breastfeeding Study, Kenya: a clinical trial. PLoS Med 2011;8:29. 
29.
de Vincenzi I. Triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis during pregnancy and breastfeeding for prevention of mother-to-child transmission of HIV-1 (Kesho Bora study): a randomised controlled trial. Lancet Infect Dis 2011;11:171-80. 
30.
Shapiro RL, Hughes MD, Ogwu A, et al. Antiretroviral regimens in pregnancy and breast-feeding in Botswana. N Engl J Med 2010;362:2282-94. 
31.
Read JS, Newell MK. Efficacy and safety of cesarean delivery for prevention of mother-to-child transmission of HIV-1. Cochrane Database Syst Rev 2005; (4):CD005479. 
32.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. (Last updated: August 6, 2015; last reviewed: August 6, 2015) Access via: http://aidsinfo.nih.gov/guidelines
33.
de Ruiter A, Taylor GP, Clayden P, et al; British HIV Association. British HIV Association guidelines for the management of HIV infection in pregnant women 2012 (2014 interim review). HIV Med 2014;15 Suppl 4:1-77. Available at: https://aidsinfo.nih.gov/contentfiles/lvguidelines/glchunk/glchunk_487.pdf (last accessed 3 March 2016).  
34.
The International Perinatal HIV Group. The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1--a meta-analysis of 15 prospective cohort studies. N Engl J Med 1999;340:977-87. 
35.
Briand N, Jasseron C, Sibiude J, et al. Cesarean section for HIV-infected women in the combination antiretroviral therapies era, 2000-2010. Am J Obstet Gynecol 2013;209(4):335.e1-335.e12. 
36.
Dahlke JD, Mendez-Figueroa H, Rouse DJ, Berghella V, Baxter JK, Chauhan SP. Evidence-based surgery for cesarean delivery: an updated systematic review. Am J Obstet Gynecol 2013;209:294-306. 
37.
Townsend CL, Cortina-Borja M, Peckham CS, de Ruiter A, Lyall H, Tookey PA. Low rates of mother-to-child transmission of HIV following effective pregnancy interventions in the United Kingdom and Ireland, 2000-2006. AIDS 2008;22:973-81. 
38.
Nduati R, John G, Mbori-Ngacha D, et al. Effect of breastfeeding and formula feeding on transmission of HIV-1: a randomized clinical trial. Jama 2000;283:1167-74. 
39.
Coovadia HM, Rollins NC, Bland RM, et al. Mother-to-child transmission of HIV-1 infection during exclusive breastfeeding in the first 6 months of life: an intervention cohort study. Lancet 2007;369:1107-16. 
40.
Thomas TK, Masaba R, Borkowf CB, et al. Triple-antiretroviral prophylaxis to prevent mother-to-child HIV transmission through breastfeeding--the Kisumu Breastfeeding Study, Kenya: a clinical trial. PLoS Med 2011;8:29. 
41.
de Vincenzi I. Triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis during pregnancy and breastfeeding for prevention of mother-to-child transmission of HIV-1 (Kesho Bora study): a randomised controlled trial. Lancet Infect Dis 2011;11:171-80. 
42.
Shapiro RL, Hughes MD, Ogwu A, et al. Antiretroviral regimens in pregnancy and breast-feeding in Botswana. N Engl J Med 2010;362:2282-94. 
43.
Nduati R, John G, Mbori-Ngacha D, et al. Effect of breastfeeding and formula feeding on transmission of HIV-1: a randomized clinical trial. Jama 2000;283:1167-74. 
44.
Coovadia HM, Rollins NC, Bland RM, et al. Mother-to-child transmission of HIV-1 infection during exclusive breastfeeding in the first 6 months of life: an intervention cohort study. Lancet 2007;369:1107-16. 
45.
Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med 1994;331:1173-80. 
46.
Garcia PM, Kalish LA, Pitt J, et al. Maternal levels of plasma human immunodeficiency virus type 1 RNA and the risk of perinatal transmission. Women and Infants Transmission Study Group. N Engl J Med 1999;341:394-402. 
47.
de Ruiter A, Taylor GP, Clayden P, et al; British HIV Association. British HIV Association guidelines for the management of HIV infection in pregnant women 2012 (2014 interim review). HIV Med 2014;15 Suppl 4:1-77. Available at: https://aidsinfo.nih.gov/contentfiles/lvguidelines/glchunk/glchunk_487.pdf (last accessed 3 March 2016). 
48.
Townsend CL, Byrne L, Cortina-Borja M, et al. Earlier initiation of ART and further decline in mother-to-child HIV transmission rates, 2000-2011. AIDS 2014;28:1049-57. 
49.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. (Last updated: August 6, 2015; last reviewed: August 6, 2015) Access via: http://aidsinfo.nih.gov/guidelines 
50.
de Ruiter A, Taylor GP, Clayden P, et al; British HIV Association. British HIV Association guidelines for the management of HIV infection in pregnant women 2012 (2014 interim review). HIV Med 2014;15 Suppl 4:1-77. Available at: https://aidsinfo.nih.gov/contentfiles/lvguidelines/glchunk/glchunk_487.pdf (last accessed 3 March 2016). 
51.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. (Last updated: August 6, 2015; last reviewed: August 6, 2015) Access via: http://aidsinfo.nih.gov/guidelines
52.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. (Last updated: August 6, 2015; last reviewed: August 6, 2015) Access via: http://aidsinfo.nih.gov/guidelines
53.
de Ruiter A, Taylor GP, Clayden P, et al; British HIV Association. British HIV Association guidelines for the management of HIV infection in pregnant women 2012 (2014 interim review). HIV Med 2014;15 Suppl 4:1-77. Available at: https://aidsinfo.nih.gov/contentfiles/lvguidelines/glchunk/glchunk_487.pdf (last accessed 3 March 2016). 
54.
Floridia M, Ravizza M, Pinnetti C, et al Treatment change in pregnancy is a significant risk factor for detectable HIV-1 RNA in plasma at end of pregnancy. HIV Clin Trials 2010;11:303-11. 
55.
Bardeguez AD, Lindsey JC, Shannon M, et al Adherence to antiretrovirals among US women during and after pregnancy. J Acquir Immune Defic Syndr 2008;48:408-17. 
56.
Bonner K, Mezochow A, Roberts T, Ford N, Cohn J. Viral load monitoring as a tool to reinforce adherence: a systematic review. J Acquir Immune Defic Syndr 2013;64:74-8. 
57.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. (Last updated: August 6, 2015; last reviewed: August 6, 2015) Access via: http://aidsinfo.nih.gov/guidelines
58.
de Ruiter A, Taylor GP, Clayden P, et al; British HIV Association. British HIV Association guidelines for the management of HIV infection in pregnant women 2012 (2014 interim review). HIV Med 2014;15 Suppl 4:1-77. Available at: https://aidsinfo.nih.gov/contentfiles/lvguidelines/glchunk/glchunk_487.pdf (last accessed 3 March 2016). 
59.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. (Last updated: August 6, 2015; last reviewed: August 6, 2015) Access via: http://aidsinfo.nih.gov/guidelines. 
60.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. (Last updated: August 6, 2015; last reviewed: August 6, 2015) Access via: http://aidsinfo.nih.gov/guidelines
61.
Crauwels HM, Baugh B, Ryan R, et al. Total and unbound PK of once daily Darunavir/Ritonavir in HIV-1infected pregnant women.  5th International Workshop on HIV and Women, Seattle, USA; 23-26 February, 2015. Oral abstract O1. Available at: http://regist2.virology-education.com/2015/5thHIVwomen/03_Crauwels.pdf (last accessed 3 March 2016). 
62.
Rangopal M, O Osiyemi O, Zorrilla C, et al. Pharmacokinetics of etravirine in HIV infected pregnant women.  5th International Workshop on HIV and Women, Seattle, USA, 23-26 February, 2015. Available at: http://www.croiconference.org/sessions/pharmacokinetics-etravirine-hiv-1–infected-pregnant-women (last accessed 3 March 2016). 
63.
Williams PL, Crain MJ, Yildirim C, et al. Congenital anomalies and in utero antiretroviral exposure in human immunodeficiency virus-exposed uninfected infants. JAMA Pediatr 2015;169:48-55 
64.
Williams PL, Crain MJ, Yildirim C, et al. Congenital anomalies and in utero antiretroviral exposure in human immunodeficiency virus-exposed uninfected infants. JAMA Pediatr 2015;169:48-55 
65.
Ford N, Mofenson L, Shubber Z, et al. Safety of efavirenz in the first trimester of pregnancy: an updated systematic review and meta-analysis. AIDS 2014; 28 (Suppl 2):S123-131. 
66.
Floridia M, Ravizza M, Masuelli G et al. Atazanavir and lopinavir profile in pregnant women with HIV: tolerability, activity and pregnancy outcomes in an observational national study. J Antimicrob Chemother 2014;69:1377-84. 
67.
Kourtis AP, Schmid CH, Jamieson DJ, Lau J. Use of antiretroviral therapy in pregnant HIV-infected women and the risk of premature delivery: a meta-analysis. AIDS 2007;21:607-15. 
68.
Townsend CL, Cortina-Borja M, Peckham CS, Tookey P. Antiretroviral therapy and premature delivery in diagnosed HIV-1 infected women in the United Kingdom and Ireland. AIDS 2007;21:1019-26. 
69.
Hitti J, Anderson J, McComsey G, et al. Protease inhibitor-based therapy and glucose intolerance in pregnancy: AIDS Clinical Trials Group A5084 Am J Obstet Gynecol. 2007;196 : e331-337. 
70.
Read JS. Diagnosis of HIV-1 infection in children younger than 18 months in the United States. Pediatrics 2007;120:e1547-62. 
71.
Burgard M, Blanche S, Jasseron C, et al. Performance of HIV-1 DNA or HIV-1 RNA tests for early diagnosis of perinatal HIV-1 infection during anti-retroviral prophylaxis. J Pediatr 2012;160:60-6.40. 
72.
Cohen MS, Chen YQ, McCauley M et al. Prevention of HIV-1 infection with early antiretroviral therapy. N. Engl J Med 2011;365:493-505. 
73.
Rodger A, Cambiano V, Bruun T, et al; ; PARTNER study group. HIV transmission risk through condomless sex if the HIV positive partner is on suppressive ART: PARTNER study. Partner Study interim results, 21st Conference on Retroviruses and Opportunistic infections (CROI). 3-6 March 2104, Boston USA. 
74.
Hankins C. Use of Pre-exposure Prophylaxis (PrEP) in pregnancy for primary prevention of HIV infection in women. 5th International Workshop on HIV and Women. Seattle USA, 23-26 February 2015. Available at: http://regist2.virology-education.com/2015/5thHIVwomen/07_Hankins.pdf (last accessed 3 March 2016). 
75.
Hankins C. Use of Pre-exposure Prophylaxis (PrEP) in pregnancy for primary prevention of HIV infection in women. 5th International Workshop on HIV and Women. Seattle USA, 23-26 February 2015. Available at: http://regist2.virology-education.com/2015/5thHIVwomen/07_Hankins.pdf (last accessed 3 March 2016). 
76.
Hankins C. Use of Pre-exposure Prophylaxis (PrEP) in pregnancy for primary prevention of HIV infection in women. 5th International Workshop on HIV and Women. Seattle USA, 23-26 February 2015. Available at: http://regist2.virology-education.com/2015/5thHIVwomen/07_Hankins.pdf (last accessed 3 March 2016). 
77.
Abdool Karim Q, Abdool Karim SS, Frolich JA et al. Effectiveness and safety of Tenofovir gel, an antiretroviral microbicide for the prevention of HIV infection in women. Science 2010;329:1168-74. 
78.
Lampe MA, Smith DK, Anderson GJ, Edwards AE, Nesheim SR.  Achieving safe conception in HIV-sero-discordant couples: the potential role of oral pre-exposure prophylaxis (PrEP) in the United States. Am J Obstet Gynecol 2011;204:e481-488.