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Richtlijn zorg voor patiënten met hiv in de eerste lijnPublished by: Werkgroep Ontwikkeling Richtlijnen Eerste Lijn (Worel)Last published: 2023GPC sur la prise en charge des patients vivant avec le VIHPublished by: Groupe de Travail Développement de recommmandations de première ligneLast published: 2023Optimizing the management of maternal HIV improves maternal health and helps to prevent perinatal and secondary sexual transmission. All pregnant women with HIV should receive antiretroviral therapy (ART) to prevent perinatal transmission. ART reduces perinatal transmission by decreasing maternal viral load in the blood and genital secretions. ART should be initiated as early as possible in the pregnancy, regardless of CD4 count or viral load, and should be administered during the antepartum, intrapartum, and postpartum periods, as well as neonatal prophylaxis for the infant. The goal of ART is to achieve and maintain viral suppression to undetectable levels (i.e., HIV RNA <50 copies/mL).[7] An infectious diseases consultation is strongly recommended early in pregnancy.
General principles of ART in pregnant women
Women with HIV who are receiving ART and have achieved virologic suppression should continue their ART during pregnancy provided that it is safe, effective in suppressing viral replication, and well tolerated. Discontinuation of ART may lead to viral rebound and increased risk of intrauterine HIV transmission. However, certain antiretroviral drugs are not recommended in pregnancy due to a high risk of toxicity, and some of the newer ART regimens lack significant experience in pregnancy and/or may need additional dosing or therapeutic drug level monitoring secondary to decreased plasma concentrations in the second and third trimesters. Switching to drug regimens that are recommended in pregnancy should be considered in these situations; however, this should only be done under specialist guidance to ensure continued viral suppression and tolerability. (See Antepartum ART section.) Resistance testing is recommended before switching regimens if HIV RNA is above the threshold for standard genotypic drug resistance testing (see Investigations). If the regimen is modified during pregnancy, viral load should be monitored more frequently (e.g., every 1-2 months) until stable viral suppression occurs.[7]
Women who are not currently taking ART should be started on a regimen as soon as HIV is a feasible diagnosis regardless of CD4 count or viral load; earlier viral suppression is associated with a lower risk of perinatal transmission. (See Antepartum ART section.) Treatment should not be delayed due to concerns about teratogenicity with first-trimester exposure. Resistance testing should be performed to help guide selection of drugs, but initiation of ART should be started empirically and not delayed for results of resistance testing (see Investigations). Regimens can be modified once results of resistance testing are available.[7]
Women who present for pregnancy care during the early first trimester should be counseled on the risks (e.g., potential teratogenic effects, maternal adverse effects, increased risk of preterm delivery) and benefits (e.g., improved maternal health, reduced risk of perinatal transmission) of ART during early pregnancy. Multiple studies indicate no difference in rates of total birth defects for first-trimester exposure compared with later drug exposures and national birth defect registry data. However, data on the risks of birth defects for many newer drugs are limited and evolving.[7] All cases of ART drug exposure during pregnancy should be reported to the Antiretroviral Pregnancy Registry. Antiretroviral Pregnancy Registry Opens in new window There are mixed data regarding the increased risk of preterm delivery and low birth weight/small for gestational age with ART. Given the clear benefits of ART in pregnancy for both the health of the mother and prevention of perinatal transmission, ART should not be withheld before conception or early in pregnancy due to concerns for potential adverse pregnancy outcomes. However, patients should be counseled regarding the potential risks and enhanced prenatal surveillance may be considered.[7][86][87][88][89][90][91][92][93] See Complications.
If an ART drug regimen must be stopped during pregnancy (e.g., for severe toxicity), all drugs should be stopped simultaneously. A complete, effective ART regimen should be reinitiated as soon as possible. Women should continue taking antepartum ART during labor and delivery as prescribed.[7]
A specialist should be consulted for the management of special populations including pregnant women with hepatitis B or C coinfection, renal or hepatic impairment, perinatally acquired infection, or HIV-2 infection; pregnant women who present to care and who are already on ART (or have been in the past); and nonpregnant women who are trying to conceive. These patient groups are beyond the scope of this topic.
Antepartum ART
Pregnancy should not preclude the use of drug regimens that would be chosen for nonpregnant people, unless the the risks outweigh the benefits or adequate drug levels are not likely to be attained during pregnancy. Shared decision-making following discussion of the potential risks and benefits to the patient and fetus is important when choosing drug regimens, acknowledging the limited data available.[7]
Regimens are complex, and consultation with an infectious diseases specialist is recommended. The US National Institutes of Health guidelines suggest the following principles:[7]
In general, the same regimens as recommended for treatment of nonpregnant adults should be used in pregnant women unless there are known adverse effects for women, fetuses, or infants that outweigh benefits
Multiple factors must be considered when choosing a regimen for a pregnant woman including comorbidities, convenience, adverse effects, drug interactions, resistance testing results, pharmacokinetics, and experience with use in pregnancy
Pharmacokinetic changes in pregnancy may lead to lower plasma levels of drugs and necessitate increased dosages, more frequent dosing, or boosting, especially of protease inhibitors.
For ART-naive women without resistance, a combination regimen including 2 nucleoside reverse transcriptase inhibitors (NRTIs), known as an NRTI backbone, and an integrase strand transfer inhibitor (INSTI), is preferred. A protease inhibitor (PI) with low-dose ritonavir boosting or a non-nucleoside reverse transcriptase inhibitor (NNRTI) may be used as an alternative option to an INSTI. Based on the US National Institutes of Health guidelines, recommended preferred and alternative options for ART in pregnant women (and those trying to conceive) include:[7]
NRTIs
Preferred options: emtricitabine/tenofovir disoproxil; emtricitabine/tenofovir alafenamide; lamivudine/tenofovir disoproxil; lamivudine plus tenofovir alafenamide
Alternative option: abacavir/lamivudine; lamivudine/zidovudine
INSTIs
Preferred options: dolutegravir, bictegravir
Alternative option: raltegravir
PIs
Preferred option: there are no preferred options for use in treatment-naive pregnant women
Alternative options: ritonavir-boosted atazanavir; ritonavir-boosted darunavir (may be a preferred option in certain circumstances - for example, people with a history of cabotegravir exposure for pre-exposure prophylaxis [PrEP] when genotype testing is not available or demonstrates INSTI resistance)
NNRTIs
Preferred options: there are no preferred options for use in treatment-naive pregnant women
Alternative options: efavirenz; rilpivirine
The preferred initial regimen for treatment-naive pregnant women depends on previous use of long-acting cabotegravir for PrEP.[7]
No history of prior use of long-acting cabotegravir as PrEP: dolutegravir or bictegravir plus a tenofovir-containing dual NRTI backbone - e.g., dolutegravir plus tenofovir disoproxil or tenofovir alafenamide plus emtricitabine or lamivudine, or bictegravir/tenofovir alafenamide/emtricitabine.
History of prior use of long-acting cabotegravir as PrEP: ritonavir-boosted darunavir plus tenofovir disoproxil or tenofovir alafenamide plus emtricitabine or lamivudine, pending results of genotype and INSTI-resistance mutation testing.
These same regimens may be used in pregnant women with early (acute and recent) HIV infection. However, use of an empiric INSTI-containing regimen is not recommended unless genotype testing shows no evidence of INSTI resistance. Other regimens may be recommended in special circumstances and specific situations (e.g., postpartum period, treatment-experienced patients): a detailed discussion of all recommended ART regimens is beyond the scope of this topic. Local guidelines should be consulted.
The World Health Organization (WHO) supports the use of dolutegravir plus tenofovir disoproxil plus emtricitabine or lamivudine as a preferred first-line option for all adults, including pregnant women and women of childbearing age. Lamivudine plus tenofovir disoproxil plus efavirenz (low dose) is an alternative first-line option.[94]
There are no data about the use of two-drug regimens in pregnancy. However, pregnant women who present to care on a two-drug regimen and have successfully maintained viral suppression may continue the regimen with more frequent viral load monitoring (e.g., every 1-2 months) throughout pregnancy.[7]
Preliminary data from a birth outcomes surveillance study in Botswana raised concern of an increased risk of neural tube defects (0.9%) in infants born to women who were receiving dolutegravir at the time of conception. However, updated results from the study have shown that the prevalence of neural tube defects in infants who were exposed to dolutegravir at the time of conception is not significantly different from those on non-dolutegravir-based regimens.[7] In one US cohort study, no clear differences in birth outcomes were reported with dolutegravir-based regimens compared with non-dolutegravir-based regimens; however, sample sizes were small.[95]
There are insufficient pharmacokinetic and safety data to recommend newer drugs such as cabotegravir, cabotegravir/rilpivirine, doravirine, enfuvirtide, etravirine, fostemsavir, ibalizumab, lenacapavir, and maraviroc in pregnant women at this time. However, some drugs may be recommended in special circumstances (e.g., extensive treatment experience, resistance). Patients who present to care and who are on long-acting injectable cabotegravir/rilpivirine should be counseled about the extremely limited and insufficient data with this regimen, and either continue the regimen with frequent viral load monitoring or switch to one of the preferred or alternative three-drug regimens, using a shared decision-making process. Cabotegravir and rilpivirine must be stopped 1 year before conception in patients considering switching regimens prior to conception to prevent fetal exposure to these drugs. Cobicistat-based regimens are not generally recommended in pregnant women due to pharmacokinetic changes in the second and third trimesters, which may cause lower drug exposures and subsequent virologic failure. However, some women may choose to continue this drug with frequent viral load monitoring and possible dose adjustments, rather than switching to a preferred or alternative regimen.[7]
Scheduled cesarean delivery
A scheduled cesarean delivery at 38 weeks' gestation (compared with 39 weeks for most other indications) is recommended for pregnant women with HIV who have HIV RNA levels >1000 copies/mL or unknown viral load near the time of delivery, in order to reduce the risk of perinatal transmission.[7] In nonvirally suppressed patients who present in labor prior to their scheduled cesarean delivery date, an emergency cesarean delivery should be performed. However, there are insufficient data to address the question of how long after the onset of labor or rupture of membranes the benefit of cesarean delivery for prevention of perinatal transmission is lost. Urgent consultation with a perinatal HIV specialist is recommended.
Individualized birth plans to extend pregnancies beyond 38 weeks and to avoid the need for cesarean delivery may be considered in women with HIV RNA >1000 copies/mL or unknown viral load who have started intrapartum ART.[7]
Scheduled cesarean delivery is not routinely recommended for women on ART who have HIV RNA levels ≤1000 copies/mL because of the low rate of perinatal transmission in these patients, as well as limited or no known evidence of benefit, and an increased risk of infection, surgical trauma, hospital deaths, and prolonged hospitalization associated with cesarean delivery.[7][15][96] If scheduled cesarean delivery or induction is indicated in these patients, it should be performed at the standard time for obstetric indications.
Intrapartum maternal ART
Intravenous zidovudine (started at least 3 hours before scheduled delivery) is recommended in women with HIV RNA >1000 copies/mL or unknown viral load near delivery (within 4 weeks of delivery). It is also recommended if there is a known or suspected lack of adherence to ART since the last HIV RNA result, or the patient tests positive during labor. It is not recommended in women receiving ART with HIV RNA ≤50 copies/mL during late pregnancy and near delivery, provided there are no concerns about adherence to ART. Intravenous zidovudine may be considered in women with HIV RNA between 50 and ≤1000 copies/mL within 4 weeks of delivery; however, there are inadequate data to determine whether this provides additional protection against perinatal transmission in this group. Women should continue taking their antepartum ART on schedule during labor and before scheduled delivery.[7]
Antiretroviral regimens for infants: in utero or intrapartum exposure to HIV
All infants who have been perinatally exposed to HIV should receive postpartum antiretroviral prophylaxis in the immediate neonatal period to reduce the risk of perinatal transmission. Antiretroviral prophylaxis should be started as close to the time of delivery as possible, and preferably within 6 hours of birth. A HIV test is recommended at birth for all infants; however, it is not necessary for infants at low risk of HIV acquisition who are not being breastfed. Consult with a pediatric infectious disease specialist is recommended.[7]
Choice of antiretroviral regimen for initial postnatal prophylaxis in infants with in utero or intrapartum exposure to HIV is based on the predicted risk for transmission as determined by the mother’s HIV RNA levels.[7]
Infants at high risk of HIV acquisition (i.e., born to a pregnant woman with HIV RNA ≥50 copies/mL in the 4 weeks prior to delivery):
A three-drug regimen consisting of zidovudine plus lamivudine plus either nevirapine (treatment dose) or raltegravir is recommended, administered from birth for 2-6 weeks. This serves as presumptive HIV therapy or enhanced prophylaxis.
If the HIV test at birth is negative and the duration of prophylaxis is <6 weeks, zidovudine monotherapy should be continued to complete a 6-week course.
Infants at low risk of HIV acquisition (i.e., born to a pregnant woman with HIV RNA <50 copies/mL from 20 weeks’ gestation through to delivery, ideally documented by at least 2 consecutive tests at least 4 weeks apart but can be based on clinical judgement):
Zidovudine monotherapy for 2 weeks is recommended.
Infants who do not meet the criteria above should receive antiretroviral regimens and durations based on case-specific factors related to the level and timing of viremia during pregnancy.
Consult your local guidance for more information.
Antiretroviral regimens for infants: exposure to HIV during breastfeeding
Choice of antiretroviral regimen for extended prophylaxis during breastfeeding in infants with exposure to HIV during the breastfeeding period is based on the current or anticipated virologic status of the breastfeeding parent. HIV RNA levels of the breastfeeding parent should be monitored periodically during breastfeeding. Extended antiretroviral prophylaxis during breastfeeding should ensure continuous prophylaxis through the entire postnatal period. Infants should be transitioned to the options recommended below only after completion of initial postnatal prophylaxis with zidovudine (see section above).[7]
Infants at low risk of HIV acquisition during breastfeeding (i.e., breastfeeding parent is receiving ART with HIV RNA <50 copies/mL for at least 3 months prior to delivery and there are no concerns about ART adherence):
There is no consensus about management in these patients. Nevirapine or lamivudine are the recommended options. However, some experts do not recommend extended prophylaxis in these patients.
Infants currently at low risk of HIV acquisition during breastfeeding but with concerns for future risk (i.e., concerns about lack of ART adherence or loss of virologic suppression for other reasons during breastfeeding):
Nevirapine or lamivudine should be considered.
Extended prophylaxis should continue until either 6 weeks after the last exposure to breast milk, or 6 weeks after concerns about the breastfeeding parent’s virologic suppression have resolved, whichever comes first. It may be reasonable to discontinue prophylaxis earlier if the concerns for viremia in the breastfeeding parent have resolved.
Nevirapine or lamivudine can be given from birth (replacing zidovudine) to provide initial postnatal prophylaxis and extended prophylaxis during breastfeeding. Consult your local guidelines for more information.
If the breastfeeding parent experiences new viremia during breastfeeding, breastfeeding should be temporarily stopped or discontinued, replacement feeding initiated, and an HIV test performed in the infant. Permanent discontinuation is recommended by most experts when HIV RNA is ≥200 copies/mL, but some support resuming breastfeeding once virologic suppression is achieved again. The choice of antiretroviral regimen depends on the level of maternal viremia.[7]
New viremia during breastfeeding with HIV RNA ≥200 copies/mL:
In infants age <4 weeks, zidovudine plus lamivudine plus nevirapine (treatment dose) or raltegravir for 2-6 weeks is recommended.
In infants age ≥4 weeks, a three-drug regimen consisting of zidovudine plus lamivudine plus dolutegravir for 2-6 weeks is recommended.
If the HIV test is negative and the duration of prophylaxis is <6 weeks, zidovudine monotherapy can be continued to complete a 6-week course.
New viremia during breastfeeding with HIV RNA <200 copies/mL:
There is no consensus about management in these patients. Some experts recommend a three-drug regimen (as for those with HIV RNA ≥200 copies/mL), while others recommend a single-drug regimen with either nevirapine or lamivudine. Others recommend management based on repeat HIV RNA testing of the breastfeeding parent. Consultation with an expert is recommended.
Infants of mothers with a new diagnosis of HIV during breastfeeding should be managed as per the recommendations for infants at high risk of in utero or intrapartum HIV acquisition above, along with replacement feeding.[7]
The selection of ART for newborns with presumed or confirmed HIV infection is beyond the scope of this topic.
Breast-feeding
Several studies in low‐resource settings with exclusive breast-feeding in women with HIV demonstrated next to no perinatal HIV transmission with maternal viral suppression on ART.[38][97][98] However, while suppressive ART significantly reduces the risk of perinatal HIV transmission through breast-feeding, it does not completely eliminate the risk (estimated to be 3/1000).[7]
US guidelines recommend that patients should receive patient-centered, evidence-based counseling to support shared decision-making about infant feeding, including breast-feeding. Counseling should include information about available feeding options, including formula feeding, use of banked donor milk, or breastfeeding.[7]
Replacement feeding is recommended to eliminate the risk of HIV transmission via breast-feeding when people with HIV are not on ART and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester) and at delivery. However, patients who are on ART with a sustained undetectable viral load should be supported if they choose to breast-feed.[7]
If the breastfeeding parent has a detectable viral load, replacement feeding should be initiated and breastfeeding temporarily stopped or discontinued while viral load is rechecked and causes for the viremia are investigated. If the repeat viral load is undetectable, breastfeeding may resume. If the repeat viral load is detectable, options may include initiating or modifying infant antiretroviral prophylaxis, permanently discontinuing breastfeeding, and considering the need for infant HIV testing.
Most experts recommend permanently discontinuing breastfeeding if HIV RNA is ≥200 copies/mL.
Measures to minimize risk of HIV transmission (e.g., exclusive breast-feeding for the first 6 months, gradual weaning, immediate treatment of maternal mastitis and infant thrush, infant monitoring) are recommended in women who choose to breast-feed.[7]
The American Academy of Pediatrics (AAP) supports a harm reduction approach in people on ART with sustained viral suppression <50 copies/mL, but recommends counseling people against breast-feeding if they are not on ART or are on ART without viral suppression.[99]
Transgender and gender diverse people assigned female sex at birth
It is generally appropriate to extrapolate the recommendations above to all people assigned female sex at birth, including transgender and gender diverse people, with modification when indicated (e.g., drug interactions with gender-affirming hormones). Some patients may experience the onset or worsening of gender dysphoria and associated symptoms (e.g., depression) during prepregnancy, antepartum, and postpartum periods, and should be monitored appropriately.[7] This topic currently uses gender-specific terms; however, the topic is intended to be inclusive of all birthing parents, regardless of gender identity. It is important to assess and use an individual’s preferred terminology.
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