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Special Considerations in the Management of HIV in Women, Including During Conception and Pregnancy

Joseph J. Eron, Jr., MD
Program Director
Daniel R. Kuritzkes, MD
Program Director
Judith S. Currier, MD, MSc
Sigal Yawetz, MD
Released: May 21, 2020

Care of Pregnant Women With HIV

During the past 25-30 years, guidelines for the treatment of pregnant women with HIV and prevention of perinatal transmission have evolved considerably. The current recommendations focus on ensuring use of ART by known pregnant women with HIV, regardless of maternal health needs, to reduce the risk of mother-to-child transmission; identifying HIV infection in pregnant women with previously undiagnosed or newly acquired HIV infections; preventing HIV transmission to infants through the use of chemoprophylaxis ART; and avoiding breastfeeding. These recommendations have resulted in a significant decrease in perinatal transmission rates—to less than 2%—in the United States and the United Kingdom.[183] The DHHS guidelines provide an overview of the most common circumstances that occur in the care of pregnant women with HIV.[52]

Screening for HIV in Pregnant Women
Current guidelines from the CDC,[184] the Committee on Obstetric Practice and HIV Expert Work Group from the American College of Obstetricians and Gynecologists,[185] and the DHHS[52] recommend routine prenatal HIV screening in the first trimester in all women and repeat testing in the third trimester of pregnancy in women who are at increased risk of acquiring HIV, including those who are receiving care in facilities that have an HIV incidence of ≥ 1 case per 1000 pregnant women per year, those who are incarcerated, those who reside in jurisdictions with elevated HIV incidence, or those who reside in states that require third-trimester testing. One study demonstrated an HIV incidence rate of 16.75 per 1000 person-years during pregnancy in a group of women in Swaziland who were HIV negative at initial testing. In total, 4.4% of women who were HIV negative at study entry were HIV positive at the time of delivery.[186] Other studies have shown higher rates of HIV acquisition in pregnant women (2.3 per 1000 person-years) when compared with nonpregnant (1.1 per 1000 person-years) or lactating (1.3 per 1000 person-years) women.[187] These data suggest that pregnant women may be at increased risk for HIV transmission and that repeat testing is warranted in sexually active women during pregnancy. The DHHS recommends repeat testing at other times during pregnancy when clinically indicated, such as when a woman presents with symptoms potentially indicating an STD, when a woman is diagnosed with an STD, or when a woman presents with symptoms suggestive of acute HIV infection.[52]

Women who present to labor and delivery with unknown HIV status or who are at risk for HIV should undergo rapid testing.[52,185] Those with a positive rapid test should receive ARV prophylaxis (eg, intravenous zidovudine).[185,188] Initiation of zidovudine should not be delayed for testing confirmation. If HIV infection diagnosis is established, women should be linked to a specialist for ongoing HIV care and comanagement.[185]

Initial Evaluation of Pregnant Women With HIV
The medical care of a pregnant woman with HIV should integrate the expertise of the obstetrical providers and the HIV specialists to decrease the risk of HIV transmission and obstetrical complications. Known behavioral risk factors that increase the risk of perinatal HIV transmission—at least in studies conducted before the ART era—include[189-193]:

  • Cigarette smoking
  • Illicit drug use
  • Genital tract infections
  • Unprotected intercourse with multiple partners during pregnancy

Therefore, counseling to avoid tobacco and illicit drug use, encouraging the use of condoms during sexual intercourse, and screening for genital tract infections should be integrated into care.

Biological factors associated with perinatal transmission of HIV are primarily determined by maternal health. These factors include:

  • Past and present CD4+ cell counts
  • Plasma HIV-1 RNA
  • ARV resistance
  • Past and present opportunistic infections

Initial management should also include screening for hepatitis B virus, hepatitis C virus, and tuberculosis. A thorough history of adverse events during previous ARV regimens should also be gathered.

ART During Pregnancy
ART should be initiated in all pregnant women with HIV regardless of CD4+ cell count or HIV-1 RNA level. ARV resistance testing should be obtained before initiating ART. Complete blood cell count and renal and liver function testing should also be obtained before treatment initiation. Appropriate opportunistic infection prophylaxis should be started based on current CD4+ cell count.

Decisions regarding which ARV combinations are most effective in pregnancy are complex and should be made in consultation with a provider who has an understanding of these complexities (Table 4).[52,194] The efficacy of ART in preventing maternal–fetal transmission is primarily through lowering plasma HIV-1 RNA but also due to PrEP for the infant. The mechanism by which infant PrEP is effective is through ARV agents crossing the placenta, resulting in adequate systemic concentrations in the infant. This is especially important at the time of delivery when the infant is exposed to maternal blood and genital tract secretions. Because it is unclear what HIV-1 RNA level may be considered “safe” from concerns about transplacental transmission, all pregnant women with HIV should be offered ART. The most recent DHHS Perinatal ART guidelines state that consideration should be given to starting ART as soon as HIV is diagnosed during pregnancy because earlier viral suppression is associated with reduced risk of transmission to the fetus.[52] The guidelines also note that the benefits of early treatment must be weighed against potential effects of drug exposure on the fetus. Data from a 2014 study involving 806 infants found that infants exposed to ART during the first trimester of pregnancy did not have an increased risk of birth defects compared with unexposed infants (odds ratio: 1.07; 95% CI: 0.50-2.31).[195] For women who remain viremic during pregnancy or are diagnosed with HIV late in pregnancy, a raltegravir-containing or dolutegravir-containing regimen can rapidly decrease viral load.[52,196] There is no evidence that pregnancy decreases the efficacy of ART regimens recommended during pregnancy.[52,197]

The recommendations for initiation of ART for maternal health are similar between pregnant and nonpregnant women with HIV. Pregnancy should not preclude the use of optimal drug regimens. However, additional factors specific to pregnancy must be considered.

  • For women who are pregnant, the regimen should be individualized based on previous ART and any comorbidities. For ARV-naive women who are pregnant, a combination regimen with 2 NRTIs and a boosted PI or an INSTI is preferred. One or more NRTIs with high levels of transplacental passage should be used.
  • In women who present with acute HIV infection during pregnancy, it is important to rapidly suppress HIV-1 RNA to reduce the risk of perinatal HIV transmission. Dolutegravir plus emtricitabine/tenofovir DF is the preferred ARV regimen for pregnant and breastfeeding women with acute HIV infection. Raltegravir plus emtricitabine/tenofovir DF or a regimen that includes a ritonavir-boosted PI are considered alternative regimens. Consultation with an HIV specialist is also recommended in women who are diagnosed with acute HIV infection during pregnancy or breastfeeding because of the high risk for perinatal HIV transmission. The HIV specialist may also counsel on appropriate infant regimens and management. Enhanced adherence counseling is also recommended for women diagnosed in the perinatal period.[52]
  • Typically, the most appropriate course of action for women with HIV who are virologically suppressed on ART and subsequently become pregnant is to continue the current ARV regimen, regardless of agent(s) because of the (small) risk of virologic breakthrough that may accompany any regimen modification. The current exception to that rule is the use of regimens containing cobicistat.[52] Inadequate levels of both cobicistat and elvitegravir in the second and third trimesters, as well as viral breakthroughs, have been reported.[120] If such a regimen is continued, HIV-1 RNA should be monitored frequently, and therapeutic drug monitoring may be useful.
  • DHHS Recommendations Regarding Dolutegravir Use in Adults and Adolescents With HIV Who Are Pregnant or of Childbearing Potential: Exposure to dolutegravir around the time of conception has been associated with a small but statistically significant increase in the risk of infant neural tube defects in Botswana (0.3%).[102,103] Although this risk was higher than the risk for neural tube defects in infants born to women who were receiving efavirenz (0.05%) and women without HIV (0.08%), based on the available evidence, dolutegravir is listed as a preferred drug for pregnant women, regardless of trimester, and as an alternative drug for women who are trying to conceive.[52]
  • Folic acid has been shown to lower the risk of neural tube defects in the general population and 400 μg/day is recommended during conception and throughout pregnancy by the US Public Health Service. However, a causal association has not been established between dolutegravir and impaired folate metabolism, and it is not known if folic acid supplementation will help prevent neural tube defects in infants of women receiving dolutegravir.[52]
  • In utero exposure to tenofovir DF is associated with significantly lower bone mineral density in infants; however, long-term implications of this finding are uncertain.[198]
  • Women should be counseled regarding the potential risk of congenital anomalies in infants exposed to efavirenz in the first trimester. However, there are conflicting data as to the true risk. Several reports have not supported an increased risk in efavirenz-exposed infants than in the general population[199-202] whereas others have suggested an increased risk.[203,204]
    • Although the prescribing information cautions the use of efavirenz in pregnant women prior to 8 weeks’ gestational age, the DHHS panel on perinatal transmission does not restrict use of efavirenz in the first trimester based on data suggesting no increased risk of neural tube defects compared with the general population.[52] The panel also states that women who become pregnant while receiving suppressive efavirenz-based regimens should continue their current regimens. Efavirenz-containing regimens are no longer preferred regimens, however, either for the general population with HIV or for pregnant women with HIV.
    • Efavirenz may be avoided in women of childbearing potential who do not practice reliable birth control who have alternative choices of ARV agents. However, efavirenz may be a preferred choice in some women, such as in a late diagnosis of HIV and the need for rapid viral decay or those with tuberculosis coinfection.[205,206]
  • Some NRTIs, such as zidovudine, have demonstrated increased efficacy in preventing transmission independent of their antiviral effects because of the high levels of transplacental passage. Zidovudine was an integral part of ART regimens for many years but has been moved to the alternative category due to increased toxicity vs newer NRTIs. Regardless, ARV regimens should include 2 NRTIs with high levels of transplacental passage (zidovudine, lamivudine, emtricitabine, tenofovir DF, or abacavir). Triple-NRTI–only regimens should be avoided.
  • Drugs such as stavudine, didanosine, or full-dose ritonavir, which are no longer used due to toxicity, should also be stopped in women who present during pregnancy while receiving these medications.
  • When choosing ARV regimens, other comorbid conditions, such as hepatitis B, and possible adverse outcomes for mother and fetus should be considered.
    • If women with HIV/hepatitis B virus coinfection are virally suppressed on a regimen containing tenofovir AF and become pregnant, they can be offered the choice of continuing that drug or switching to tenofovir DF, as there are limited data on the use of tenofovir AF in pregnancy.[52]
  • Some data show that PI use is associated with preterm delivery but not increased hospitalizations or infant mortality. PI use is proven to be beneficial, but clinicians should be aware of this potential risk and be prepared to manage the patients appropriately to maximize benefits of ART during pregnancy.[207]
  • Potential adverse events and the woman’s ability to adhere to a particular regimen during pregnancy should be considered.[77]

Table 4. Recommendations for Use of ARV Agents in Pregnancy[52]

Close

Monitoring During Pregnancy
Pregnant women with HIV require additional considerations during pregnancy. Those receiving ART should be monitored regularly for treatment response and complications.[52]

  • Ultrasound
    • First trimester (or as soon as possible thereafter) ultrasound is recommended for confirmation of gestational age
    • Second trimester ultrasound is recommended to assess fetal anatomy
  • Laboratory monitoring
    • Complete blood cell count to evaluate for anemia, especially if taking zidovudine
    • Renal toxicity
    • Serum bicarbonate, especially if receiving didanosine or stavudine, to evaluate for lactic acidosis (neither of these drugs is recommended in pregnancy)
    • Liver function tests
    • HIV-1 RNA levels should be monitored 2-4 weeks after initiating or changing ART, monthly thereafter until HIV-1 RNA is undetectable, and then at least every 3 months. At approximately 34-36 weeks’ gestation, HIV-1 RNA should be assessed such that decisions regarding mode of delivery or alterations in ART before delivery as well as optimal treatment of the newborn can be made
  • CD4+ cell count should be monitored at the initial antenatal visit
    • CD4+ cell counts do not have to be repeated in pregnancy for women who have been receiving ART for ³ 2 years and who have had viral suppression and CD4+ cell counts consistently > 300 cells/mm3
    • CD4+ cell counts should be monitored every 3-6 months during pregnancy in women who have been receiving ART for < 2 years, women with CD4+ cell counts < 300 cells/mm3, and women with inconsistent adherence and/or detectable viral loads
  • ARV resistance testing should be performed:
    • Before initiating ART in treatment-naive women with HIV-1 RNA higher than the threshold for resistance testing (> 500-1000 copies/mL) if they have not received previous resistance testing; if ART is initiated before drug resistance testing results are available, modify the regimen based on resistance assay results, if necessary
    • Before changing ART regimens in women who become pregnant with HIV-1 RNA higher than the threshold for resistance testing (> 500-1000 copies/mL) while receiving ART or with persistently detectable HIV-1 RNA after initiating ART during pregnancy
  • Hyperglycemia
    • Although pregnancy itself is associated with hyperglycemia, the use of PIs does not appear to increase this risk
      • Women should receive standard glucose screening with a standard 1-hour, 50-gram glucose loading test at 24-28 weeks
      • Earlier testing should be considered in women with risk factors for glucose intolerance such as PI therapy, obesity, advanced maternal age, and family history of diabetes

Metabolic alterations are common during pregnancy and can be complicated by ART. Clinicians should closely monitor patients during pregnancy, tailoring treatment and recommending lifestyle alterations to manage metabolic conditions that can affect both the mother and infant.[208]

Immunizations
The immunization history of pregnant women with HIV should be reviewed at the initial prenatal visit. Women should follow the same vaccination schedule as nonpregnant individuals with HIV, with special attention given to make sure women with HIV are vaccinated against hepatitis A and B (if antibodies are not present) and influenza. Because persons with HIV and pregnant women are each individually at increased risk for influenza-related complications, pregnant women with HIV should be strongly encouraged to receive the influenza virus vaccine, inactivated.

Intrapartum Management
The PACTG 076 trial demonstrated that the use of zidovudine (antepartum, intravenous zidovudine during delivery and in the infant) decreased perinatal transmission by 67.5%.[209] As a result, intravenous zidovudine during labor and delivery (regardless of mode of delivery) is still highly recommended for women with HIV-1 RNA > 1000 copies/mL or unknown HIV-1 RNA levels unless there is evidence of resistance or toxicity.[52] (Although some practitioners administer zidovudine prophylaxis at any detectable HIV-1 RNA, there are inadequate data to suggest that administering zidovudine is advantageous when HIV-1 RNA is between 50 and 999 copies/mL).[52] For women who are virologically suppressed consistently during late pregnancy and for whom there are no adherence concerns, current ART does not require the addition of intravenous zidovudine. However, every effort should be made to administer zidovudine in appropriate patients. Neonatal ART prophylaxis is also recommended, and the duration is dependent on transmission risk level.[52] Full-term infants whose mother received a suppressive ART regimen during pregnancy should receive zidovudine prophylaxis for 4 weeks. All infants with an increased risk of HIV transmission including those whose mothers did not receive antepartum or intrapartum ART, received intrapartum ART only, or received ART but did not have sustained viral suppression should receive one of the following:

  • 2-drug ART prophylaxis with 6 weeks of zidovudine and 3 doses of nevirapine (prophylactic dosage, with doses given within 48 hours of birth, 48 hours after first dose, and 96 hours after second dose), or
  • Empiric therapy with zidovudine for 6 weeks plus lamivudine plus nevirapine for 2-6 weeks, or
  • Empiric therapy with zidovudine for 6 weeks plus lamivudine plus raltegravir for 2-6 weeks

Mode of Delivery
Women whose HIV-1 RNA remains > 1000 copies/mL should be recommended to undergo Cesarean section, whereas it is unclear if Cesarean section delivery confers added benefit in women receiving ART with plasma HIV-1 RNA ≤ 1000 copies/mL.[52] In women with HIV-1 RNA > 1000 copies/mL, a Cesarean section should be scheduled at 38 weeks’ gestation, if possible. Intravenous zidovudine should be used, with infusion initiated 3 hours before the scheduled Cesarean section delivery (2 mg/kg over 1-hour loading dose, then 1 mg/kg/hour continuous infusion until delivery, ie, umbilical cord ligated).

In women whose HIV-1 RNA is ≤ 1000 copies/mL, Cesarean section delivery required for standard obstetric indications should be performed at the standard time for obstetrical indications. Invasive fetal monitoring, operative delivery with vacuum devices or forceps, and episiotomy should be avoided in women with HIV, as these may increase risk of transmission.[52,210,211] Duration of ruptured membranes is not associated with perinatal transmission, and vaginal delivery is recommended.[52,212-214] Intravenous infusion with zidovudine should be initiated at the onset of labor, using the dosing schedule outlined for Cesarean section.

Concurrent ART and Other Medications
Women should continue their oral ART regimen as prescribed before and during the labor/delivery process.[52] The intravenous zidovudine infusion should replace oral zidovudine. Therefore, women receiving a fixed-dose combination pill of lamivudine/zidovudine should receive lamivudine 150 mg every 12 hours rather than the lamivudine/zidovudine combination pill formulation. Additional ARV agents should be administered as prescribed with the exception of stavudine. Zidovudine and stavudine are antagonistic and, therefore, should not be used concurrently. Methylergonovine should be avoided in women receiving PIs, efavirenz, or cobicistat unless no alternative treatments for postpartum hemorrhage are available and the need for pharmacologic treatment outweighs the risk of exaggerated vasoconstrictive response.[52] If absolutely required, the lowest possible dose of methylergonovine should be used.

In addition, women who present to labor and delivery who are not receiving ART or have suboptimal viral suppression should receive the following:

  • Intravenous zidovudine infusion (2 mg/kg loading dose followed by 1 mg/kg/hour continuous infusion) should be initiated as soon as possible
  • Cesarean section delivery
  • Infants should receive one of the following unless testing confirms positivity
    • Zidovudine for 6 weeks and 3 doses of nevirapine (prophylactic dosage, with doses given within 48 hours of birth, 48 hours after first dose, and 96 hours after second dose), or
    • Empiric therapy with zidovudine for 6 weeks plus lamivudine plus nevirapine for 2-6 weeks
    • Empiric therapy with zidovudine for 6 weeks plus lamivudine plus raltegravir for 2-6 weeks

       

Women who have positive rapid HIV testing at labor and delivery should receive confirmatory testing after delivery.

Postpartum Management
Current recommendations highlight the need for ART for all patients with HIV, because untreated HIV infection or uncontrolled viremia may be associated with adverse outcomes including increased risk of cardiovascular disease, liver disease, and neurologic complications.[77] Moreover, the SMART study demonstrated that among patients with a prior CD4+ cell count < 350 cells/mm3, interrupting ART is associated with an increased risk of immunologic impairment—resulting in risk of opportunistic disease or death from any cause—as well as a higher risk of AIDS-defining malignancies.[215-217] Therefore, there is no longer a solid rationale to stop ART in the postpartum period. However, decisions regarding the continuation of ART postpartum should involve consultation between the woman and her HIV provider, preferably before delivery, and with the following considerations in mind [52]:

  • Continuing ART in women who initiated ART for fetal protection should be recommended unless a contraindication exists; preferred regimens for nonpregnant women are similar to those for pregnant women. The mother should receive prescriptions for herself and her infant before discharge.
  • Adherence to ART should be reinforced postpartum as it often decreases during this period; clinicians should evaluate patients for issues that may reduce adherence (eg, depression or drug and alcohol use)

Breastfeeding is not recommended in any women with HIV with access to clean water and formula, regardless of HIV-1 RNA level, because of the increased risk of HIV transmission.[52] Potential barriers to formula feeding should be discussed with the mother before discharge to help mothers follow infant feeding recommendations and avoid breastfeeding.[52] However, in settings that lack such access and where breastfeeding is required for infant health, data from the PROMOTE study comparing efavirenz plus lamivudine/zidovudine with lopinavir/ritonavir plus lamivudine/zidovudine in 389 pregnant women in rural Uganda are informative. ART was initiated at 12-28 weeks’ gestation and continued to 1 year or throughout breastfeeding (women were counseled to breastfeed for 1 year). A subanalysis of the study revealed a very low HIV transmission rate of 0.5% among live-born infants, including only 1 case of transmission during breastfeeding, which occurred in the lopinavir/ritonavir-containing arm.[218] Virologic suppression rates were high at > 85% at all time points and in both treatment arms throughout the trial. The randomized, controlled BAN trial conducted in Lilongwe, Malawi also provides informative data on the role of ART in preventing HIV transmission during breastfeeding. In this study, 2369 breastfeeding mother–infant pairs with HIV (mothers required to have CD4+ cell count ≥ 250 cells/mm3) were randomized to one of the following 28-week regimens: maternal triple ART (n = 849); daily infant nevirapine (n = 852); or no extended postnatal ARV regimen (n = 668).[219] The estimated HIV transmission risk between postnatal Weeks 2-28 was significantly higher, at 5.7%, for infants in the group that received no extended postnatal ART than for infants in the maternal-regimen group (2.9%; P = .009) or for those in the infant-regimen group (1.7%; P < .001). The results demonstrated that either maternal triple ART or infant nevirapine was effective at reducing the risk of HIV transmission during breastfeeding.

Premastication of food has also been associated with HIV transmission and should be avoided. Women should be counseled regarding contraceptive choices. A dual protection strategy may be considered to protect against both unintended pregnancy and HIV transmission in the postpartum period.

Women who tested positive with an expedited HIV antibody test during labor should receive intravenous zidovudine immediately and require immediate linkage to HIV care with comprehensive follow-up.[52] These patients should also not breastfeed unless a confirmatory HIV test is negative.

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