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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

Recommendations for Use of Antiretroviral Drugs During Pregnancy

HIV-Infected Pregnant Women Who Have Never Received Antiretroviral Drugs (Antiretroviral Naive)

(Last updated: August 6, 2015; last reviewed: August 6, 2015)

Panel's Recommendations for HIV-Infected Pregnant Women Who Have Never Received Antiretroviral Drugs

Panel's Recommendations

  • All HIV-infected pregnant women should receive combination antiretroviral therapy (cART) to reduce the risk of perinatal transmission of HIV (AI). The choice of regimen should take into account current adult treatment guidelines, what is known about the use of specific drugs in pregnancy, and the risk of teratogenicity (see Table 6 and Table 7).
  • Consideration should be given to initiating cART as soon as HIV is diagnosed during pregnancy; earlier viral suppression is associated with lower risk of transmission. This decision may be influenced by CD4 T lymphocyte count, HIV RNA levels, and maternal conditions (e.g., nausea and vomiting) (AIII). The benefits of early cART must be weighed against potential fetal effects of drug exposure.
  • Antiretroviral drug-resistance studies should be performed to guide selection of antiretroviral regimens in women whose HIV RNA levels are above the threshold for resistance testing (i.e., >500 to 1,000 copies/mL) unless drug-resistance studies have already been performed (see Antiretroviral Drug Resistance and Resistance Testing in Pregnancy) (AI). If cART is initiated before the results of the drug-resistance assays are available, the antiretroviral regimen should be modified, if necessary, based on the resistance assay results (BIII).
  • If there is no evidence of resistance, cART regimens that are preferred for the treatment of antiretroviral-naive HIV-infected pregnant women include: a dual nucleoside reverse transcriptase inhibitor combination (abacavir/lamivudine, tenofovir disoproxil fumarate/emtricitabine or lamivudine, or zidovudine/lamivudine) and either a ritonavir-boosted protease inhibitor (atazanavir/ritonavir or darunavir/ritonavir), a non-nucleoside reverse transcriptase inhibitor (efavirenz initiated after 8 weeks of pregnancy), or an integrase inhibitor (raltegravir) (see Table 6) (AIII).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion

Pregnant women with HIV infection should receive standard clinical, immunologic, and virologic evaluation. They should be counseled about and offered combination antiretroviral therapy (cART) containing at least 3 drugs for their own health and for prevention of perinatal transmission of HIV, consistent with the principles of treatment for non-pregnant adults.1 Use of a cART regimen that successfully reduces plasma HIV RNA to undetectable levels substantially lowers the risk of perinatal transmission of HIV, lessens the need for consideration of elective cesarean delivery as an intervention to reduce risk of transmission, and reduces risk of antiretroviral (ARV) drug resistance in the mother. In an analysis of perinatal transmission in a total of 12,486 infants delivered by HIV-infected women between 2000 and 2011 in the United Kingdom and Ireland, the overall perinatal transmission rate declined from 2.1% in 2000–2001 to 0.46% in 2010–2011. The transmission risk was significantly lower (0.09%) in women with viral loads <50 copies/mL compared with a risk of 1.0% in women with viral loads of 50–399 copies/mL, regardless of the type of ARV regimen or mode of delivery.2 The continued decline in perinatal transmission rates was attributed to increasing number of women on cART at the time of conception and reductions in the proportion of women either initiating cART late in pregnancy or never receving cART prior to delivery. Similar data from Canada in 1,707 HIV-infected pregnant women followed between 1997 and 2010 showed perinatal transmission was 1% in all mothers receiving cART and 0.4% if more than 4 weeks of cART was received.

ARV drug-resistance testing should be performed before starting an ARV regimen if plasma HIV RNA levels are above the threshold for resistance testing (that is, >500 to 1,000 copies/mL). For details regarding genotypic and phenotypic resistance testing, see Adult and Adolescent Antiretroviral Guidelines. Given the association of earlier viral suppression with lower risk of transmission as discussed above, during pregnancy, cART should be initiated as soon as HIV is diagnosed without waiting for the results of resistance testing, with modification of the regimen, if required, when test results return. Because clinically significant resistance to protease inhibitors (PI) is less common than resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) in ARV-naive individuals, a PI-based cART regimen generally should be considered in this situation.

Table 6 outlines the ARV regimens that are preferred for treatment of HIV-infected pregnant women who have never received ARV drugs. These recommendations are based on available data indicating acceptable toxicity profiles, ease of use, pharmacokinetic data in pregnancy, and lack of evidence of teratogenic effects or established adverse outcomes for mother, fetus or newborn in addition to optimal ARV efficacy and durability. Preferred regimens include a dual nucleoside reverse transcriptase inhibitor (NRTI) combination (abacavir/lamivudine, tenofovir disoproxil fumarate (tenofovir)/emtricitabine or lamivudine, or zidovudine/lamivudine) in combination with either a ritonavir-boosted PI (atazanavir/ritonavir or darunavir/ritonavir), an NNRTI (efavirenz initiated after 8 weeks of pregnancy) or an integrase inhibitor (raltegravir). Alternative regimens include those demonstrated to be effective in adults but with more limited data on use in pregnancy, lack of or incomplete data on teratogenicity, and dosing, formulation, toxicity or interaction issues. Selection of these regimens should be based on individual patient characteristics and needs (see Table 7).

Susceptibility of fetuses to the potential teratogenic effects of drugs is dependent on multiple factors, including the gestational age of the fetus at exposure (see the Teratogenicity section). Although fetal effects of ARV drugs are not fully known, in general, reports of birth defects in fetuses/infants of women enrolled in observational studies who receive ARV regimens during pregnancy have been reassuring. There have been no differences in the rates of birth defects for first-trimester compared with either later gestational exposures or with rates reported in the general population.4-7 The decision about when to initiate cART should be carefully considered by health care providers and their patients. The discussion should include an assessment of a woman’s health status and the benefits and risks to her health and the potential risks and benefits to the fetus.

Although most perinatal transmission events occur late in pregnancy or during delivery, recent analyses suggest that early control of viral replication may be important in preventing transmission. In a French study, lack of early and sustained control of maternal viral load appeared strongly associated with residual perinatal transmission of HIV.8 That study evaluated risk factors for perinatal transmission in women with HIV RNA <500 copies/mL at the time of delivery; overall HIV transmission was 0.5%. Women who transmitted were less likely to have received ARV drugs at the time of conception than nontransmitters and were less likely to have HIV RNA <500 copies/mL at 14, 28, and 32 weeks’ gestation. By multivariate analysis, plasma viral load at 30 weeks’ gestation was significantly associated with transmission. Among women starting ARV drugs during pregnancy, the gestational age at initiation of therapy did not differ between groups (30 weeks), but viral load tended to decrease earlier in the nontransmitters, although this was not statistically significant. The number of patients initiating therapy during pregnancy was too small to assess whether initiation of ARV drugs in the first trimester was associated with lower rates of transmission. These data suggest that early and sustained control of HIV viral replication is associated with decreasing residual risk of transmission and favor initiating cART sufficiently early in ARV-naive women to suppress viral replication by the third trimester. Other studies have demonstrated that baseline viral load is significantly associated with the likelihood of viral suppression by delivery, and thus, prompt initiation of cART would be particularly important in HIV-infected pregnant women who have high baseline viral loads.9-11 However, the potential benefits of earlier initiation of cART must be balanced against the unknown long-term outcome of first-trimester ARV exposure to the fetus.

cART is recommended for all HIV-infected pregnant women, regardless of viral load. Although rates of perinatal transmission are low in women with undetectable or low HIV RNA levels, there is no threshold below which lack of transmission can be ensured.12-14 The mechanism by which ARV drugs reduce perinatal transmission of HIV is multifactorial. Although lowering maternal antenatal viral load is an important component of prevention in women with higher viral load, ARV prophylaxis is effective even in women with low viral load.15-19 Additional mechanisms of protection include pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis of the infant. With PrEP, passage of the ARV drug across the placenta results in presence of drug levels sufficient for inhibition of viral replication in the fetus, particularly during the birth process when there is intensive viral exposure. Therefore, whenever possible, cART regimens initiated during pregnancy should include zidovudine or another NRTI with high transplacental passage, such as lamivudine, emtricitabine, tenofovir, or abacavir (see Table 7).20 23 With post-exposure prophylaxis, ARV drugs are administered to the infant after birth.

Some women may wish to restrict fetal exposure to ARV drugs while reducing the risk of HIV transmission to their infants. Use of zidovudine alone during pregnancy for prophylaxis of perinatal transmission is not optimal, but it could be an option for women with low viral loads (i.e., <1,000 copies/mL) on no ARV drugs. In the UK study discussed above, transmission rates were 0.7% for women receiving a triple-ARV drug regimen combined with planned cesarean delivery or with planned vaginal delivery and 0.5% in 464 women with HIV RNA levels <10,000 copies/mL who received single-drug prophylaxis with zidovudine combined with planned cesarean delivery, not significantly different between groups. Zidovudine single-drug prophylaxis is recommended in the British HIV Association guidelines for women with CD4 T lymphocyte counts >350 cells/mm3 and HIV RNA levels <10,000 copies/mL and wild-type virus who do not require treatment for their own health.24 Time-limited administration of zidovudine during the second and third trimesters is less likely to induce development of resistance in women with low viral loads than in those with higher viral loads. This lower rate of resistance is likely because of the low level of viral replication and the short duration of exposure.25,26 Women’s choices after counseling to use or not use ARV drugs during pregnancy should be respected.

Raltegravir has been suggested for use in late pregnancy in women who have high viral loads because of its ability to rapidly suppress viral load (approximately 2-log copies/mL decrease by Week 2 of therapy).27-30 Two recent case series have reported the effect of adding raltegravir to cART regimens. In one, 4 women diagnosed with HIV infection in the third trimester experienced a mean viral load decline per week of 1.12 log after raltegravir was added to a standard ARV regimen.31 In the second publication, raltegravir was either initiated as part of a combination ARV regimen in nine ARV-naive women or added to an existing ARV regimen in five women who conceived on cART but had persistent viremia. Raltegravir was initiated at a gestational age of 34 weeks or later.32 The median exposure time to raltegravir was 17 days and the mean viral load decline was 2.6 log. Although no raltegravir-related side effects were noted in these reports, marked elevations in hepatic transaminases were reported in a single HIV-infected pregnant woman when raltegravir was added to an ARV regimen.33 Because the efficacy and safety of this approach has only been described in anecdotal reports, it cannot be routinely recommended at this time for women who are ARV-naive.

The cART regimen initiated during pregnancy can be modified after delivery to include simplified regimens that were not used in pregnancy because pregnancy safety data were insufficient. Decisions regarding continuation of an ARV regimen or which specific ARV agents to use should be made by women in consultation with their HIV care providers, taking into account current recommendations and life circumstances (see General Principles Regarding Use of Antiretroviral Drugs during Pregnancy).


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