Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission.

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 HHS Panel on the Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission – A Working Group of the Office of AIDS Research Advisory Council AETC NRC Slide Set

About This Presentation
These slides were developed from the March 28, 2014, revisions to the guidelines. The goal of the guidelines is to provide guidance to HIV care practitioners. Because the field of HIV care is changing rapidly, users of this slide set are advised to check for updates. It is intended that these slides be used as prepared, without changes in either content or attribution. Users are asked to honor this intent. AETC National Resource Center March 2014

Table of Contents Topic Slide Number Introduction
Pre-Conception Counseling Antepartum Care Intrapartum Care Postpartum Care Care of the Neonate Lessons Learned from Clinical Trials March 2014

Introduction (1) Providers considering the use of antiretrovirals (ARVs) for HIV-infected women during pregnancy must take into account: ARV treatment (ART) for maternal HIV infection; and ARV chemoprophylaxis to reduce the risk of perinatal transmission of HIV With universal prenatal HIV counseling and testing, preconception care, ARV prophylaxis, scheduled C-section delivery (if indicated), and avoidance of breast-feeding, perinatal HIV infection has diminished to <2% in the United States. March 2014

Strength of Recommendation
Introduction (2) Recommendations in these guidelines are based on scientific evidence and expert opinion and are rated using the system below: Strength of Recommendation Quality of Evidence A: Strong B: Moderate C: Optional I: One or more randomized trials with clinical outcomes and/or validated laboratory end points II: One or more well-designed, nonrandomized trials or observational studies with long-term clinical outcomes III: Expert opinion March 2014

PRECONCEPTION COUNSELING AND CARE FOR HIV-INFECTED WOMEN OF CHILDBEARING AGE

Preconception Counseling and Care (1)
Comprehensive family planning and preconception care is part of routine primary care and is recommended by CDC, ACOG, and other national organizations. Purpose: Prevention of unintended pregnancies Optimization of maternal health prior to pregnancy Prevention of perinatal transmission Prevention of HIV transmission to an uninfected partner while trying to conceive March 2014

Recommendations Discuss childbearing intentions with all women of childbearing age on an ongoing basis throughout the course of their care. (AIII) Include information about effective and appropriate contraceptive methods to reduce the likelihood of unintended pregnancy. (AI) March 2014

During preconception counseling, include information on safer sexual practices and elimination of alcohol, illicit drugs, and smoking, which are important for the health and of all women as well as for fetal/infant health, should pregnancy occur. (AII) All HIV-infected women contemplating pregnancy should be on a maximally suppressive antiretroviral regimen. (AII) March 2014

When selecting or evaluating combination (cART) for HIV-infected women of childbearing age, consider the following (AII): A regimen’s effectiveness Hepatitis B virus disease status Teratogenic potential of the drugs in the cART regimen, should pregnancy occur Possible adverse outcomes for the mother and fetus March 2014

Women who do not desire pregnancy should be offered contraception. All available methods can be used, including hormonal contraception and intrauterine devices. Interactions between some ARVs and hormonal contraceptives may lower contraceptive efficacy Emergency contraception can be used as appropriate ̶ either pills or copper IUD Again, be aware of potential interactions with ARVs that could lower contraceptive efficacy Interactions between ARVs and ulipristal acetate have not been defined but are likely March 2014

Drug Interactions between ARVs and Hormonal Contraceptives (CIII) (1)
NNRTIs: ARV Drug Recommendation for Combined Hormonal Methods and Progestin-Only Pills Recommendation for DMPA Recommendation for Etonogestrel Implants EFV Use alternative or additional contraception No additional contraceptive needed ETR No additional contraceptive needed NVP Consider alternative contraceptive, or barrier + oral hormonal methods Consider alternative contraceptive, or barrier + implant RPV March 2014

RTV-Boosted PIs: ARV Drug Recommendation for Combined Hormonal Methods and Progestin-Only Pills Recommendation for DMPA Recommendation for Etonogestrel Implants ATV/r Use alternative or additional contraception No additional contraceptive needed Consider alternative contraceptive, or barrier + implant DRV/r FPV/r LPV/r March 2014

RTV-Boosted PIs: ARV Drug Recommendation for Combined Hormonal Methods and Progestin-Only Pills Recommendation for DMPA Recommendation for Etonogestrel Implants SQV/r Use alternative or additional contraception No additional contraceptive needed Consider alternative contraceptive, or barrier + implant TPV/r March 2014

PIs without RTV: ARV Drug Recommendation for Combined Hormonal Methods and Progestin-Only Pills Recommendation for DMPA Recommendation for Etonogestrel Implants ATV No additional contraceptive needed OC should contain ≤30 μg ethinyl estradiol (EE), or use alternative method No data on OCs with <25 μg EE or progestins other than norethindrone or norgestimate FPV Use alternative contraception (use with estradiol/norethindrone may cause virologic failure) Use alternative or additional contraception March 2014

PIs without RTV: ARV Drug Recommendation for Combined Hormonal Methods and Progestin-Only Pills Recommendation for DMPA Recommendation for Etonogestrel Implants IDV No additional contraceptive needed NFV Use alternative or additional contraception March 2014

Integrase Inhibitors: ARV Drug Recommendation for Combined Hormonal Methods and Progestin-Only Pills Recommendation for DMPA Recommendation for Etonogestrel Implants RAL No additional contraceptive needed DTG EVG/COBI CCR5 Antagonist: All categories: No additional contraceptive needed March 2014

Reproductive Options for HIV-Concordant and Serodiscordant Couples (1)
For both concordant (both partners are HIV infected) and discordant couples: Expert consultation is recommended so that approaches can be tailored to specific needs, which may vary from couple to couple. (AIII) Partners should be screened for genital tract infections. (AII) The HIV-infected partner should attain maximum viral suppression before attempting conception. (AIII) March 2014

For discordant couples: cART for the infected partner may not be fully protective against sexual transmission of HIV. Periconception administration of antiretroviral preexposure prophylaxis (PrEP) for HIV-uninfected partners may offer an additional tool to reduce the risk of sexual transmission. (CIII) The utility of PrEP for the uninfected partner when the infected partner is receiving cART and has a suppressed viral load has not been studied. March 2014

Discordant couples with HIV-infected female: The safest conception option is artificial insemination, including the option of self-insemination with a partner’s sperm during the periovulatory period. (AIII) March 2014

Discordant couples with HIV-infected male: The use of donor sperm from an HIV-uninfected male with artificial insemination is the safest option. When the use of donor sperm is unacceptable, the use of sperm preparation techniques coupled with either intrauterine insemination or in vitro fertilization should be considered. (AII) Semen analysis is recommended for HIV-infected males before conception is attempted to prevent unnecessary exposure to infectious genital fluid when the likelihood of getting pregnant is low because of semen abnormalities. (AIII) March 2014

Periconception PrEP Very few data to date on periconception PrEP; studies under way Infected partner should be on ART with fully suppressed HIV viral load Only combination tenofovir/emtricitabine is currently being studied in heterosexual PrEP trials Couples should use condoms at all times except during periovulatory intercourse No reported increase in congenital anomalies for children whose mothers were exposed to tenofovir or emtricitabine during pregnancy Review Table 4 “Clinical Trials of PrEP” for more information March 2014

Laboratory testing for HIV infection, baseline renal function, and chronic HBV infection should be performed before initiating PrEP. HBV-uninfected individuals should be vaccinated. Monitor for potential side effects such as renal dysfunction and clinical toxicities. Frequent testing of HIV-uninfected partner; if result is HIV positive, discontinue PrEP to minimize drug resistance and refer for treatment. March 2014

ANTEPARTUM CARE

Principles of ARV Use during Pregnancy (1)
Initial evaluation of HIV-infected pregnant women should include assessment of HIV disease status and recommendations regarding initiation or modification of cART. (AIII) All pregnant women should receive ART to prevent perinatal transmission regardless of HIV RNA and CD4 levels. (AI) Combined antepartum, intrapartum, and infant ARV prophylaxis is recommended because ARV drugs reduce perinatal transmission by several mechanisms, including lowering maternal antepartum viral load and providing infant pre- and postexposure prophylaxis. (AI) March 2014

The known benefits and potential risks of ARV use during pregnancy should be discussed with all HIV-infected women. (AIII) In counseling patients, the importance of adherence to their ARV regimens should be emphasized. (AII) ARV drug-resistance studies should be performed before starting or modifying ARV drug regimens in women whose HIV RNA is above the threshold for resistance testing. (AIII) When HIV is diagnosed later in pregnancy, cART should be initiated promptly without waiting for results of resistance testing (BIII) *see Antiretroviral Drug Resistance and Resistance Testing in Pregnancy March 2014

Coordination of services among prenatal care providers, primary care and HIV specialty care providers, and when appropriate, mental health and drug abuse treatment services, and public assistance programs, is essential to ensure that infected women adhere to their ARV drug regimens. (AIII) March 2014

(1-888-448-8765) Clinician Consultation Center
(formerly the National Perinatal HIV Hotline) ( ) For free clinical consultation for providers caring for HIV-infected women and their infants March 2014 August 2012

General Principles of Drug Selection
Guidelines for use of cART for maternal health during pregnancy generally are the same as for women who are not pregnant Some modifications based on concerns about specific ARVs during pregnancy Consider benefits vs risks of ARV drug use during pregnancy Ensure that at least 1 NRTI with high placental transfer is included in cART regimen for sufficient infant preexposure prophylaxis Counsel women on the importance of close adherence to ARV regimen Offer support services, mental health services, smoking cessation, and drug abuse treatment plans as indicated Coordinate between HIV and OB specialists March 2014

Teratogenicity (1) All cases of ARV drug exposure during pregnancy should be reported to the Antiretroviral Pregnancy Registry at: (AIII) Efavirenz (EFV): Nonpregnant women of childbearing potential should undergo pregnancy testing before initiation of EFV and receive counseling about the potential risk to the fetus and desirability of avoiding pregnancy while on EFV-containing regimens. (AIII) Alternative ARV regimens that do not include EFV should be strongly considered in women who are planning to become pregnant or are sexually active and not using effective contraception, assuming these alternative regimens are acceptable to the provider and are not thought to compromise the woman’s health. (BIII) March 2014

Teratogenicity (2) Because the risk of neural tube defects is restricted to the first 5-6 weeks of pregnancy and pregnancy is rarely recognized before 4-6 weeks of pregnancy, and unnecessary changes in ARV drugs during pregnancy may be associated with loss of viral control and increased risk of perinatal transmission, EFV can be continued in pregnant women receiving an EFV-based regimen who present for antenatal care in the first trimester, provided the regimen produces virologic suppression. (CIII) March 2014

Teratogenicity (3) Tenofovir:
No known teratogenicity Possible decrease in length and head circumference following in utero exposure Folate antagonists (eg, TMP-SMX) may have increased risk of birth defects during first-trimester use March 2014

Nevirapine and Hepatic/Rash Toxicity (1)
Nevirapine (NVP)-based regimens should be initiated in women with CD4 counts >250 cells/µL only if the benefits outweigh the risks because of the drug’s potential for causing hepatic toxicity/hypersensitivity reaction. (AII) Women who become pregnant while receiving NVP-containing regimens and who are tolerating the regimen can continue regardless of CD4 count. (AII) March 2014

Nevirapine and Hepatic/Rash Toxicity (2)
Non-NVP ARVs should be considered for women with preexisting liver disease. Data from 3,582 pregnant women in 20 studies did not find evidence of increased risk of NVP-related events compared with nonpregnant women. March 2014

NRTI Drugs and Mitochondrial Toxicity
The combination of stavudine (d4T) and didanosine (ddl) should not be prescribed during pregnancy because of reports of lactic acidosis and maternal/neonatal mortality with prolonged use in pregnancy. (AII) Mitochondrial dysfunction should be considered in uninfected children with perinatal exposure to ARV drugs who present with severe clinical findings, particularly neurological. (AII) Long-term clinical follow-up is recommended for any child with in utero exposure to ARV drugs. (AIII) March 2014

Combination ARV Drug Regimens and Pregnancy Outcome
Clinicians should be aware of a possible small increased risk of preterm birth in pregnant women receiving protease inhibitor (PI)-based ART; however, given the clear benefits of such regimens for both a women’s health and prevention of perinatal transmission, PIs should not be withheld for fear of altering pregnancy outcome. (AII) March 2014

Recommendations for Use of ARVs during Pregnancy
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. (AIII) Multiple factors must be considered when choosing a regimen for a pregnant woman including comorbidities, convenience, adverse effects, drug interactions, resistance testing results, pharmacokinetics (PK), and experience with use in pregnancy. (AII) PK changes may lead to lower plasma drug levels of drugs and necessitate increased dosages, more frequent dosing, or boosting, especially of protease inhibitors. (AII) March 2014

ART for Pregnant Women All HIV-infected pregnant women should receive a potent combination ARV) regimen 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. Reducing HIV RNA to undetectable levels lowers the risk of perinatal transmission, lessens the need for elective C-section to reduce risk of HIV transmission, and reduces risk of ARV drug resistance in the mother. March 2014

ART for Pregnant Women (2)
The decision as to whether to start the regimen in the first trimester or delay until 12 weeks’ gestation will depend on CD4 count, HIV RNA levels, and maternal conditions. (AIII) Earlier initiation of a combination ARV regimen may be more effective in reducing transmission, but benefits must be weighed against potential fetal effects of first-trimester drug exposure. Fetuses are most susceptible to potential teratogenic effects in the first trimester. Although most transmission occurs late in pregnancy or during delivery, recent analyses suggest that early control of viral replication may be important. March 2014

ARV drug-resistance studies should be performed before starting the ARV regimen if HIV RNA is above the threshold for resistance testing unless drug-resistance studies have already been performed. (AI) If HIV is diagnosed later in pregnancy, the ARV regimen should be initiated promptly without waiting for the results of resistance testing. (BIII) March 2014

If there is no evidence of resistance, combination ARV regimens that are preferred for the treatment of ART-naive HIV-infected pregnant women include: a dual NRTI combination (abacavir/lamivudine, tenofovir/emtricitabine or lamivudine, or zidovudine/lamivudine) and either a ritonavir-boosted protease inhibitor (ritonavir-boosted atazanavir or ritonavir-boosted lopinavir) or an NNRTI (efavirenz initiated after 8 weeks of pregnancy). (AIII) * Refer to Antiretroviral Drug Resistance and Resistance Testing in Pregnancy March 2014

cART regimens should include at least 3 ARVs, as in nonpregnant adults Generally, 2 NRTIs + 1 ritonavir-boosted PI or 2 NRTIs + 1 NNRTI Individualize ARVs based on factors such as: Woman’s ARV history Possible ARV resistance Comorbidities PK changes in pregnancy, placental ARV transfer Potential adverse effects on woman and on fetus Experience in pregnancy March 2014

Preferred Drugs or Drug Combinations Clinical trial data in adults have demonstrated optimal efficacy and durability with acceptable toxicity and ease of use Pregnancy-specific PK data are available to guide dosing No established association with teratogenic effects or clinically significant adverse outcomes for mothers, fetuses, or newborns Some recommended ARVs may have toxicity in animal studies that has not been verified in humans March 2014

Initial ART for ARV-Naive Pregnant Women (1)
Preferred 2-NRTI Backbone Regimens Comments ABC/3TC Potential HSR: ABC should not be used in patients who test positive for HLA-B*5701 Available as FDC, can be given once daily TDF/FTC or TDF + 3TC Can be administered once daily TDF has potential renal toxicity, use with caution in patients with renal insufficiency ZDV/3TC Most experience for use during pregnancy Twice-daily administration Higher risk of hematologic toxicity March 2014

Preferred PI Regimens Comments ATV/r + preferred 2-NRTI backbone Once daily LPV/r + preferred 2-NRTI backbone Twice-daily administration. Once-daily LPV/r not recommended during pregnancy March 2014

Preferred NNRTI Regimen Comments EFV + preferred 2-NRTI backbone Note: May be initiated after the first 8 weeks of pregnancy Birth defects in primates; risk in humans is unclear Postpartum contraception must be ensured Preferred regimen in women requiring coadministration of drugs with significant interactions with PIs March 2014

Alternative Regimens: Clinical trial data demonstrate efficacy in adults but experience in pregnancy is limited, data are lacking or incomplete on teratogenicity, or regimen is associated with dosing, formulation, toxicity, or interaction issues March 2014

Alternative PI Regimens Comments DRV/r + preferred 2-NRTI backbone Less experience with use during pregnancy than ATV/r and LPV/r SQV/r + preferred 2-NRTI backbone Baseline ECG recommended initiation of SQV/r: potential PR and QT prolongation; contraindicated with preexisting cardiac conduction system disease Large pill burden March 2014

Alternative NNRTI Regimen Comments NVP + preferred 2-NRTI backbone Caution with initiating NVP in women with CD4 >250 cells/µL Caution when starting NVP and ABC together: both can cause HSRs within the first few weeks after initiation Alternative Integrase Inhibitor Regimen Comments RAL + preferred 2-NRTI backbone Limited data on RAL use in pregnancy; may be considered when drug interactions with PI regimens are a concern March 2014

Insufficient Data to Recommend: Drugs and drug combinations are approved for use but lack sufficient pregnancy-specific PK or safety data Not Recommended: Inferior virologic response, potentially serious maternal or fetal safety concerns, or PK antagonism, or not recommended for ARV-naive nonpregnant populations March 2014

Insufficient Data to Recommend Routine Use DTG EVG/COBI/TDF/FTC FPV/r MVC RPV Not Recommended ABC/3TC/ZDV RTV as single PI d4T ETR ddI T-20 IDV/r TPV NFV March 2014

Comments on Use during Pregnancy
Individual ARVs: Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (1) Comments on Use during Pregnancy Abacavir (ABC) PK not significantly altered. High placental transfer. No evidence of teratogenicity. Hypersensitivity reactions occur in 5-8% of nonpregnant women; much smaller percentage are fatal and usually associated with rechallenge. Testing for HLA-B*5701 identifies patients at risk; conduct before starting ABC, do not give if positive. Didanosine (ddl) PK not significantly altered. Low-moderate placental transfer. Do not use with d4T; may cause lactic acidosis and death if used together. Increased rate of birth defects compared with general population noted after 1st trimester and later exposure. March 2014

Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (2)
Comments on Use during Pregnancy Emtricitabine (FTC) PK not significantly altered. High placental transfer. No evidence of teratogenicity. Active against HBV; if hepatitis B (HBV) coinfected, flare may occur if drug stopped. Lamivudine (3TC) Active against HBV; if HBV coinfected, flare may occur if drug stopped. Stavudine (d4T) Do not use with ddl or ZDV; may cause lactic acidosis or death if used together. March 2014

Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (3)
Comments on Use during Pregnancy Tenofovir Disopril Fumarate (TDF) Preferred NRTI in combination with 3TC or FTC in women with chronic HBV infection. AUC lower in 3rd trimester; trough levels adequate. High placental transfer. No evidence of teratogenicity; in monkeys, decreased fetal growth and fetal bone porosity. One human study demonstrated decreased length and head circumference. Risk of renal toxicity; monitor renal function. Active against HBV; if HBV coinfected, hepatitis flare may occur if drug stopped. Zidovudine (AZT, ZDV) PK not significantly altered. High placental transfer. No evidence of teratogenicity. March 2014

Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) (1)
Comments on Use during Pregnancy Efavirenz (EFV) AUC decreased in 3rd trimester. Moderate placental transfer. FDA Pregnancy Class D: CNS or other malformations observed in 3 of 20 monkeys; 6 human reports + 1 case report of CNS defects and 1 report of anophthalmia. Counsel nonpregnant women on risks and conduct pregnancy test prior to initiation of EFV. Consider alternative regimen in women planning to become pregnant and those who are sexually active and not using effective contraception, assuming alternatives are acceptable to provider and will not compromise health of the woman. Continue EFV in pregnant women receiving and EFV-based regimen who present for care in 1st trimester if there is virologic suppression on the regimen. March 2014

Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) (2)
Comments on Use during Pregnancy Etravirine (ETR) Safety and PK data in pregnancy insufficient; no significant changes in 4 women. Moderate placental transfer. Teratogenicity data insufficient in humans; no evidence of teratogenicity in rats or rabbits. Nevirapine (NVP) PK not significantly altered. High placental transfer. No evidence of teratogenicity. Increased risk of potentially life-threatening hepatotoxicity (often rash-associated) in women with high CD4 count at the time of NVP initiation. If CD4 is >250 cells/µL, start NVP only if benefit outweighs risk. Elevated transaminase levels at baseline may also increase risk. Women who become pregnant while on NVP and are tolerating it well can continue, regardless of CD4 count. March 2014

Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) (3)
Comments on Use during Pregnancy Rilpivirine (RPV) No PK studies in human pregnancy. Unknown placental transfer and insufficient data to assess for teratogenicity in humans. No evidence of teratogenicity in rats or rabbits. March 2014

Protease Inhibitors (1)
Class concerns for PIs: hyperglycemia, diabetes mellitus, diabetic ketoacidosis, question of increased risk of preterm delivery Recommendations for Use during Pregnancy Atazanavir (ATV) Decreased ATV plasma concentrations during pregnancy. Also reduced when given concomitantly with TDF or H2-receptor antagonist. Low placental transfer. No evidence of human teratogenicity. Must be given with RTV boosting during pregnancy. Unknown effect of in utero ATV exposure on infant indirect bilirubin levels; nonpathologic elevations of hyperbilirubinemia observed in some neonates. March 2014

Comments on Use during Pregnancy Darunavir (DRV) Limited safety and PK data during pregnancy but some experts recommend twice-daily dosing. Low placental transfer. Insufficient data to assess teratogenicity risk in humans; no evidence of teratogenicity in mice, rats, or rabbits. Must be combined with low-dose RTV. Fosamprenavir (FPV) AUC reduced during 3rd trimester. Low placental transfer. Insufficient data to assess teratogenicity risk in humans; increased fetal loss in rabbits; no increase in defects in rats and rabbits. Must be given with RTV boosting during pregnancy. March 2014

Comments on Use during Pregnancy Indinavir (IDV) Minimal placental transfer. No evidence of human teratogenicity. Must be given with RTV boosting during pregnancy. Theoretical concern regarding increased bilirubin in neonates. Ritonavir-boosted lopinavir (LPV/r) Low placental transfer. No evidence of human teratogenicity. Must be given twice daily during pregnancy, dosage increase may be needed in 2nd and 3rd trimesters. Oral solution contains 42% alcohol and 15% propylene glycol and is not recommended for use during pregnancy. March 2014

Comments on Use during Pregnancy Nelfinavir (NFV) Lower NFV exposure in 3rd trimester. Twice daily dosing. Minimal to low placental transfer. No evidence of human teratogenicity. Contains aspartame, should not be used in individuals with phenylketonuria. Ritonavir (RTV) Recommended only as PK booster for other PIs. Oral solution not optimal during pregnancy owing to alcohol content. March 2014

Comments on Use during Pregnancy Saquinavir (SQV) SQV exposure may be reduced in pregnancy but not significantly. Low placental transfer. Insufficient data to assess for teratogenicity in humans; no evidence of teratogenicity in rats or rabbits. Must be combined with low-dose RTV boosting. PR and/or QT interval prolongations have been observed; baseline ECG recommended before starting. Contraindicated if cardiac conduction system disease. SQV contraindicated in patients with preexisting cardiac conduction system disease. Twice-daily dosing. Tipranavir (TPV) No PK data in human pregnancy. Minimal-low placental transfer. No data on human teratogenicity. March 2014

Integrase Inhibitors Comments on Use during Pregnancy
Dolutegravir (DTG) No data in pregnancy; insufficient data to recommend use. Elvitegravir plus cobicistat (EVG/COBI) Raltegravir (RAL) Limited PK data suggest no significant changes in pregnancy. High placental transfer. Insufficient data to assess teratogenicity. March 2014

Comments on Use during Pregnancy
Entry Inhibitors Comments on Use during Pregnancy Enfurvirtide (T-20) No PK or teratogenicity data. Minimal/low placental transfer. Insufficient data to recommend use Maraviroc (MVC) Limited PK data, no teratogenicity data. Minimal/low placental transfer. March 2014

HIV-Infected Pregnant Women Who Are Currently Receiving Antiretroviral Therapy (1)
HIV-infected pregnant women receiving cART who present for care in the 1st trimester should continue treatment during pregnancy, assuming the regimen is tolerated and effective in suppressing viral replication (HIV-1 viral load less than lower limits of detection of the assay).(AII) It is recommended that efavirenz be continued in pregnant women receiving efavirenz-based cART who present for antenatal care in the first trimester provided the regimen is achieving virologic suppression. (CIII) HIV antiretroviral drug resistance testing is recommended for pregnant women who have detectable viremia on therapy. (AI) >500-1,000 copies/mL March 2014

HIV-Infected Pregnant Women Who Are Currently Receiving Antiretroviral Therapy (2)
Rationale for continuing EFV in pregnancy: 1st-trimester exposure is not definitely associated with increased risk of neural tube defects. The risk of neural tube defects is limited to the first 5-6 weeks of pregnancy, before most pregnancies are recognized. Unnecessary ARV changes during pregnancy may increase the risk of loss of virologic control and transmission to infant. March 2014

Pregnant Women Who Are ARV-Experienced but Not Currently on ARVs (1)
Obtain an accurate history of all prior ARV regimens used for treatment of HIV disease or prevention of transmission, including virologic efficacy, tolerance, results of prior resistance testing, and any adherence issues. (AIII) If HIV RNA is above the threshold for resistance testing (ie, >500 to 1,000 copies/mL), do ARV drug-resistance studies before starting ART (see Antiretroviral Drug Resistance and Resistance Testing in Pregnancy). (AIII) In women who present late in pregnancy, therapy or prophylaxis should be initiated promptly without waiting for the results of resistance testing. (BIII) March 2014

Choose and initiate a combination ARV regimen based on results of resistance testing and prior history of ART while avoiding drugs with teratogenic potential or with known adverse potential for the mother. (AII) Consult specialists in treatment of HIV infection about the choice of a cART regimen for women who previously received ARV drugs for their own health. (AIII) Perform repeat ARV resistance testing (AI), assess adherence, and consult with an HIV treatment specialist to guide changes in ARV drugs in women who do not achieve virologic suppression on their ARV regimens. March 2014

Pregnant women with HIV infection who have received ARVs previously for prevention of perinatal transmission: Concern that time-limited use may lead to genotypic resistance and reduced efficacy in subsequent pregnancies. Rates of resistance appear to be low after prophylaxis with cART. NVP prophylaxis may cause resistance and failure of subsequent NVP-based cART. Longer, more complex ARV tails after stopping pregnancy-limited NVP appear to reduce risk of resistance. March 2014

Treatment failure has not been demonstrated with reinitiation of cART following prophylactic use of cART in pregnancy. Pregnant women with HIV infection who have received ARVs previously for their own health: Choice of ARV regimen may be challenging and will vary by: History of ART Indication for stopping treatment Efficacy of previous ART Results of past and current resistance testing Lab testing, including HLA-B*5701 March 2014

Maternal and Fetal Monitoring during Pregnancy (1)
More frequent VL monitoring in pregnancy is recommended to identify women in whom the decline in VL is slower than expected. Viral suppression generally achieved in weeks in ARV-naive adherent individuals; rare cases take longer. March 2014

Monitor VL: At the initial visit (AI) 2-4 weeks after initiating or changing ARV regimen (BI) Monthly until VL is undetectable (BIII) At least every 3 months during pregnancy (BIII) VL should also be assessed at approximately weeks’ gestation to inform decisions about mode of delivery (AIII) March 2014

Monitor CD4 count: At initial antenatal visit (AI) At least every 3 months during pregnancy (BIII) Can monitor every 6 months in patients on stable cART with consistently suppressed VL and immune reconstitution (CD4 count increase well above threshold for opportunistic infection risk) (CIII) March 2014

Genotypic resistance testing should be performed at baseline in all HIV-infected pregnant women with HIV RNA levels >500 to 1,000 copies/mL, whether they are ARV naive or currently on therapy. (AIII) However, it is not necessary to repeat a genotype in pregnancy if the woman already had a genotype prior to pregnancy and was ARV naive. Repeat testing if suboptimal viral suppression on cART or persistent viral rebound to detectable levels after prior viral suppression on an ARV regimen. (AII) March 2014

Monitoring for complications of ARV drugs should be based on what is known about the adverse effects of the drugs a woman is receiving. (AIII) Women taking cART during pregnancy should undergo standard glucose screening at weeks’ gestation. (AIII) Some experts would perform earlier glucose screening in women receiving PI-based regimens initiated before pregnancy, similar to recommendations for women with high risk factors for glucose intolerance. (BIII) Early ultrasound is recommended to confirm gestational age and, if scheduled cesarean delivery is necessary, to guide its timing. (AII) March 2014

In women on effective cART, no perinatal transmissions have been reported after amniocentesis, but a small risk of transmission cannot be ruled out. If amniocentesis is indicated, it should be done only after initiation of an effective cART regimen and, if possible, when HIV RNA levels are undetectable. (BIII) If amniocentesis is deemed necessary with detectable VL, consult with an expert. Consider using cell-free, fetal DNA as a noninvasive alternative to decrease need for amniocentesis. March 2014

ARV Resistance during Pregnancy (1)
Drug resistance: Is one of the major factors leading to treatment failure May limit future maternal treatment options and decrease effectiveness of ARV prophylaxis during current and future pregnancies. Increased risk of resistance during pregnancy with: Nausea and vomiting (poor ARV adherence or absorption) PK changes Postpartum: If taking ARVs with low genetic barrier to resistance and simultaneous discontinuation of drugs with different half-lives March 2014

HIV drug-resistance studies should be performed before starting ARV regimens in all ARV-naïve pregnant women whose HIV RNA levels are above the threshold for resistance testing unless they have already been tested for ARV resistance. (AIII) HIV drug-resistance studies should be performed before modifying ARV regimens for those entering pregnancy with a detectable VL that is above the threshold for resistance testing while receiving ARV drugs and those who have suboptimal viral suppression after starting ARV drugs during pregnancy. (AII) In women who present late in pregnancy, an empiric ARV regimen should be initiated promptly without waiting for the results of resistance testing, with adjustment as needed after test results are available, for optimal prevention of perinatal transmission and maternal health. (BIII) March 2014

Women who have documented AZT resistance and are on regimens that do not include AZT for their own health should still receive intravenous AZT during labor along with their established ARV regimens if they have HIV RNA >1,000 copies/mL near delivery unless a history of hypersensitivity is documented. (AII) The optimal prophylactic regimen for newborns of women with ARV resistance is unknown. Therefore, ARV prophylaxis for an infant born to a woman with known or suspected drug resistance should be determined in consultation with a pediatric HIV specialist, preferably before delivery. (AIII) HIV-infected pregnant women should be given cART to maximally suppress viral replication, which is the most effective strategy for preventing development of resistance and minimizing risk of perinatal transmission. (AII) March 2014

All pregnant and postpartum women should be counseled about the importance of adherence to prescribed ARV medications to reduce the potential for development of resistance. (AII) Several studies demonstrated that women’s adherence to cART may worsen in the postpartum period. Clinicians should specifically address adherence including evaluating specific factors that facilitate or impede adherence. March 2014

To minimize development of resistance, pregnant women who receive an NNRTI-based combination ARV regimen that is discontinued after delivery should receive either dual NRTI agents alone (AI) or with a PI (BII) for 7-30 days (AII) after stopping the NNRTI drug. NNRTIs have longer half-lives than other ARVs. The optimal interval between stopping an NNRTI and the other ARV drugs is unknown. March 2014

Failure of Viral Suppression (1)
High baseline VL and later start of ART reduce the likelihood of HIV RNA suppression at delivery. Suppression of HIV RNA to undetectable levels should be achieved as quickly as possible. Evaluate and support ART adherence. March 2014

If an ultrasensitive VL assay indicates failure of viral suppression (persistent HIV RNA >20-75 copies/mL, depending on the assay used) after an adequate period of treatment: Assess resistance and adherence (AII) Consult an HIV treatment expert (AIII) Scheduled C-section is recommended for HIV-infected pregnant women who have HIV RNA >1,000 copies/mL near the time of delivery. (AII) March 2014

Addition of RAL in late pregnancy if the HIV RNA is high or if incomplete virologic suppression: RAL can rapidly suppress HIV RNA Efficacy and safety of this approach have not been evaluated and it is not routinely recommended In setting of drug resistance, addition of RAL may lead to RAL resistance March 2014

Stopping ARVs during Pregnancy (1)
HIV-infected women on cART who present for care during the 1st trimester should continue treatment during pregnancy. (AII) Although EFV should be avoided during the 1st trimester when possible, ART should not be interrupted in women taking EFV who present in the 1st trimester, if the HIV RNA is suppressed. Discontinuation of ART during pregnancy may be indicated in some situations. If an ARV drug regimen is stopped acutely for severe or life-threatening toxicity, severe pregnancy-induced hyperemesis unresponsive to antiemetics, or other acute illnesses that preclude oral intake, all ARV drugs should be stopped and reinitiated at the same time. (AIII) March 2014

If an ARV drug regimen is being stopped for non-life-threatening reasons and the patient is receiving an NNRTI, consider either: Stopping the NNRTI first and continuing the other ARV drugs for a period of time; or Switching from an NNRTI to a protease inhibitor (PI) before interruption and continuing the PI with the other ARV drugs for a period of time before electively stopping. March 2014

The optimal interval between stopping an NNRTI and the other ARV drugs is unknown; at least 7 days is recommended. Given the potential for prolonged detectable EFV concentrations for >3 weeks in patients receiving EFV-based therapy, some experts recommend continuing the other ARV agents or substituting a PI plus 2 other agents for up to 30 days after stopping the NNRTI drug. (CIII) If NVP is stopped and more than 7 days have passed before restarting therapy, NVP should be restarted with the 2-week half-dose escalation period. (AII) March 2014

HIV/Hepatitis B Virus Coinfection (1)
All HIV-infected pregnant women should be screened during pregnancy for hepatitis B virus (HBV) and hepatitis C virus (HCV) unless they are known to be coinfected or have already been screened during the current pregnancy. (AIII) All pregnant women who screen negative for HBV surface antibody should receive the HBV vaccine series. (AII) Women with chronic HBV also should be screened for hepatitis A virus (HAV) because they are at increased risk of complications from coinfection with other viral hepatitis infections. (AIII) HAV vaccine series if negative for HAV IgG March 2014

The management of HIV/HBV coinfection in pregnancy is complex ;consultation with an expert in HIV and HBV is strongly recommended. (AIII) Interferon-alfa and pegylated interferon-alfa are not recommended during pregnancy. (AIII) All pregnant women with HIV/HBV coinfection should receive cART, including a dual NRTI/NtRTI backbone with 2 drugs active against both HIV and HBV. (AII) TDF + 3TC or FTC preferred (A1) Initiation of an ARV regimen that does not include anti-HBV drugs may be associated with reactivation of HBV and development of IRIS March 2014

Pregnant women with HIV/HBV coinfection receiving ARVs should be counseled about signs and symptoms of liver toxicity, and liver transaminases should be assessed 1 month following initiation of ARV drugs and at least every 3 months thereafter during pregnancy. (BIII) If ARVs are discontinued postpartum in women with HIV/HBV coinfection, frequent monitoring of liver function tests for potential exacerbation of HBV infection is recommended, with prompt reinitiation of treatment for both HIV and HBV if a flare is suspected. (BIII) March 2014

Decisions concerning mode of delivery in HIV/HBV-coinfected pregnant women should be based on standard obstetric and HIV-related indications alone. (BIII) Within 12 hours of birth, infants born to women with HBV infection should receive hepatitis B immune globulin and the first dose of the HBV vaccine series. The second and third doses of vaccine should be administered at ages 1 and 6 months, respectively. (AI) Postvaccination testing for anti-HBs and HBsAg should be performed after completion of the vaccine series, at age 9 months to 18 months. March 2014

HIV/Hepatitis C Virus Coinfection (1)
All HIV-infected pregnant women should be screened during pregnancy for HCV if they have not been screened during the current pregnancy unless they are known to be coinfected. (AIII) Use the most sensitive immunoassays to detect HCV antibody. (AIII) All pregnant women who screen negative for HBV should receive the HBV vaccination series (AII). Women with chronic HCV infection also should be screened for hepatitis A virus (HAV) because they are at increased risk of complications from coinfection with other viral hepatitis infections. (AIII) March 2014

The management of HIV/HCV coinfection in pregnancy is complex, given currently approved medications for HCV. If considering treatment of HCV in a coinfected pregnant woman, consultation with an expert in HIV and HCV is strongly recommended. (AIII) Interferon-alfa and pegylated interferon-alfa are not recommended and ribavirin is contraindicated during pregnancy. (AII) No pregnancy data on newer oral agents Recommendations for ARV use during pregnancy are the same for women with and without HCV coinfection (BIII). March 2014

Pregnant women with HIV/HCV coinfection receiving ARV drugs should be counseled about signs and symptoms of liver toxicity, and liver transaminases should be assessed 1 month following initiation of ARV drugs and at least every 3 months thereafter during pregnancy. (BIII) Decisions concerning mode of delivery in HIV/HCV-coinfected pregnant women should be based on standard obstetric and HIV-related indications alone. (BIII) March 2014

Infants born to women with HIV/HCV coinfection should be evaluated for HCV infection with anti-HCV antibody testing after age 18 months. (AII) Infants who screen positive should undergo confirmatory HCV RNA testing. HCV RNA virologic testing can be done after age 2 months, if earlier diagnosis is indicated. (AIII) HCV viremia can be intermittent, so 2 negative HCV RNA test results at or after age 2 months, including one at or after age 12 months, are needed to definitively exclude HCV infection. (BIII) Children are considered to be HCV infected if they have 2 or more positive HCV RNA result results or are HCV antibody positive beyond age 18 months. (AII) March 2014

HIV-2 Infection and Pregnancy (1)
HIV-2 infection should be suspected in pregnant women who are from ̶ or have partners from ̶ countries in which the disease is endemic, who are HIV antibody positive on an initial enzyme-linked immunoassay screening test, and who have repeatedly indeterminate results on HIV-1 Western blot along with HIV-1 RNA viral loads at or below the limit of detection. (BII) A regimen with 2 NRTIs and a boosted PI is recommended for HIV-2-infected pregnant women who require treatment for their own health because they have significant clinical disease or CD4 count of <500 cells/µL. (AIII) March 2014

Preferred ART regimen for HIV-2-infected pregnant women who require treatment: Lopinavir/ritonavir + AZT/3TC or ABC/3TC or TDF/FTC (AIII) March 2014

Optimal prophylactic regimens have not been defined for HIV-2-infected pregnant women who do not require treatment for their own health (ie, CD4 counts >500 cells/µL and no significant clinical disease). Experts have recommended: 2 NRTIs plus lopinavir/ritonavir for prophylaxis, with the drugs stopped postpartum (BIII); or Zidovudine prophylaxis alone during pregnancy and intrapartum (BIII) March 2014

NNRTIs and enfuvirtide are not active against HIV-2 and should not be used for treatment or prophylaxis. (AIII) All infants born to HIV-2-infected mothers should receive the standard 6-week zidovudine prophylactic regimen. (BIII) In the United States, where safe infant formula is readily available, breast-feeding is not recommended for infants of HIV-2-infected mothers. (AIII) March 2014

HIV-2 is endemic in West African countries and occurs in France and Portugal; rare in the United States. In the United States, 166 cases met CDC criteria for HIV-2 diagnosis between 1998 and 2010. March 2014

FDA approved tests for HIV-2 Alere Determine HIV-1/2 Ag/Ab Combo: Rapid test that can detect HIV-1 and HIV-2 antibodies and HIV-1 p24 antigen Can be used on serum, plasma, and venous or fingerstick specimens Does not distinguish between antibodies to HIV-1 and HIV-2 Multispot HIV-1/HIV-2 Rapid Test: Distinguishes between HIV-1 and HIV-2 antibodies March 2014

Other available HIV-2 supplemental tests are not FDA approved. Commercially available HIV-1 viral load assays do not reliably detect or quantify HIV-2. No validated HIV-2 genotype or phenotype resistance assays are available in the United States. State or local health departments can arrange for additional testing by the CDC. March 2014

Acute HIV Infection (1) When acute retroviral syndrome is suspected in pregnancy or during breast-feeding, a plasma HIV RNA test should be obtained in conjunction with an HIV antibody test. (AII) Repeat HIV antibody testing during the 3rd trimester is recommended for pregnant women with initial negative HIV antibody test results (AII): Who are known to be at risk of acquiring HIV Who are receiving care in facilities that have an HIV incidence among pregnant women of at least 1 per 1,000 per year Who are incarcerated Who reside in jurisdictions with elevated HIV incidence March 2014

Acute HIV Infection (2) All pregnant women with acute or recent HIV infection should start a combination ARV regimen as soon as possible to prevent perinatal transmission, with the goal of suppressing plasma VL to below detectable levels. (AI) In women with acute HIV infection, baseline genotypic resistance testing should be performed simultaneously with initiation of the combination ARV regimen, and the ARV regimen should be adjusted, if necessary, to optimize virologic response. (AIII) Because clinically significant resistance to PIs is less common than resistance to NNRTIs in ARV-naive individuals in general, an RTV-boosted PI-based regimen should be initiated. (AIII) March 2014

Acute HIV Infection (3) Primary or acute HIV infection during pregnancy or breast-feeding is associated with increased risk of transmission. Counsel all pregnant or breast-feeding women about prevention of HIV. Reinforce importance of using condoms. Consider the use of pre- or postexposure ARV prophylaxis for those whose partners are HIV infected. Maintain a high level of suspicion for acute HIV in women who have a compatible clinical syndrome, even if high-risk behaviors are not reported. March 2014

INTRAPARTUM CARE

Intrapartum ARV Therapy/Prophylaxis (1)
Women should continue their antepartum combination ARV drug regimen on schedule as much as possible during labor and before scheduled cesarean delivery. (AIII) Intravenous (IV) AZT should be administered to HIV-infected women with VL >1,000 copies/mL (or unknown VL) near delivery (AI), but is not required for HIV-infected women receiving combination ARV regimens who have VL ≤1,000 copies/ mL consistently during late pregnancy and near delivery and no concerns regarding adherence to the regimen. (BII) March 2014

For women who have suboptimal viral suppression near delivery, scheduled cesarean delivery is recommended. (AI) Women whose HIV status is unknown who present in labor should undergo rapid HIV antibody testing. (AII) If positive result: Do a confirmatory HIV test ASAP and initiate maternal (IV AZT) and infant (combination ARV prophylaxis) ARV drugs pending results of the confirmatory test. (AII) If the confirmatory HIV test result is positive, infant ARV drugs should be continued for 6 weeks (AI); if the confirmatory result is negative, infant ARV drugs should be stopped. March 2014

Studies demonstrating use of IV AZT: The benefit of adding IV AZT in women on cART regimens has not been evaluated in randomized studies. In nonrandomized studies of women on cART, addition of intrapartem AZT appears to reduce risk of perinatal transmission if HIV RNA is not consistently suppressed to <1,000 copies/mL near time of delivery. March 2014

Transmission and Mode of Delivery (1)
Scheduled cesarean delivery is recommended for women at 38 weeks’ gestation to minimize perinatal HIV transmission with HIV RNA levels >1,000 copies/mL or unknown levels near the time of delivery, irrespective of administration of antepartum ARVs. (AII) March 2014

For pregnant women receiving cART with HIV RNA levels <1,000 copies/mL near the time of delivery: Data are insufficient to evaluate the potential benefit of scheduled cesarean delivery for prevention of perinatal transmission; unclear if it would confer additional benefit (BIII) Low rates of transmission C-sections performed for standard obstetrical indications should be scheduled for 39 weeks’ gestation March 2014

Unclear whether cesarean delivery after rupture of membranes or onset of labor reduces HIV transmission. Management should be based on: Duration of rupture and/or labor Plasma HIV RNA level Current ARV regimen (BII) If unscheduled cesarean delivery is performed and IV AZT administration is indicated, consider giving only the loading dose before proceeding with delivery. March 2014

Inform pregnant women of the risks associated with cesarean delivery. If the indication is for prevention of perinatal transmission of HIV, the risks should be balanced with potential benefits expected for the neonate. (AII) March 2014

Other Intrapartum Management Considerations (1)
Avoid the following because of potential increased risk of transmission (unless there are clear OB indications): Artificial rupture of membranes (BIII) Routine use of fetal scalp electrodes (BIII) Operative delivery with forceps or vacuum extractor and/or episiotomy (BIII) March 2014

Other Intrapartum Management Considerations (2)
When treating excessive postpartum bleeding, consider the ARVs a woman is receiving: If receiving a cytochrome (CYP) 3A4 enzyme inhibitor (eg, a PI), use methergine only if no alternative treatments are available and the need for pharmacologic treatment outweighs the risks. (BIII) If receiving a CYP3A4 enzyme inducer such as NVP, EFV, or etravirine, additional uterotonic agents may be needed because of the potential for decreased methergine levels and inadequate treatment effect. March 2014

POSTPARTUM CARE

Postpartum Care (1) Decisions about continuing ARVs ideally should be made before delivery, in consultation with the woman and her HIV provider. (AIII) cART is recommended for all HIV-infected individuals, for individual health and to prevent sexual transmission. Take into account current recommendations for the initiation of cART, pretreatment CD4 counts and trajectory, HIV RNA levels, adherence issues, whether a woman has an HIV-uninfected sex partner, and patient preference. March 2014

Postpartum Care (2) For women continuing ARV drugs postpartum, arrangement for new or continued supportive services should be made before hospital discharge because the immediate postpartum period poses a unique challenge to adherence. (AII) Counsel women about the challenge of adherence in the postpartum period. Remain vigilant for signs of depression and drug or alcohol use. Consider simplifying cART regimens to improve adherence. March 2014

Postpartum Care (3) Contraceptive counseling should be included in the prenatal period and immediately postpartum as a critical aspect of postpartum care. (AIII) The postpartum period is a critical time to address: Safer sex practices Secondary transmission prevention Contraception Review possible drug interactions of specific ARV drugs with hormonal contraceptives before prescribing Encourage dual-protection strategy of condom use plus a second highly effective contraceptive. March 2014

Postpartum Care (4) Women with a positive rapid HIV antibody test result during labor require immediate linkage to HIV care and comprehensive follow-up including: Confirmation of the diagnosis Full health assessment Evaluation for associated medical conditions Counseling related to HIV diagnosis Assessment of need for cART and opportunistic infection prophylaxis (AII) March 2014

Postpartum Care (5) Breast-feeding is not recommended for HIV-infected women in the United States, including those on cART. (AII) The presence of intracellular HIV DNA in the breast milk, may continue to pose a risk for transmission. Health care providers should routinely inquire about premastication, instruct HIV-infected caregivers against this feeding practice, and advise on safer feeding options. March 2014

CARE OF THE NEONATE

Infant Antiretroviral Prophylaxis (1)
6 weeks of neonatal AZT chemoprophylaxis is generally recommended for all HIV-exposed neonates to reduce perinatal transmission of HIV. (AI) March 2014

Infants born to women who received standard cART during pregnancy with consistent viral suppression and there are no concerns related to maternal adherence: 6 weeks of neonatal AZT chemoprophylaxis Can consider a 4-week neonatal AZT chemoprophylaxis regimen (BII) March 2014

Infants born to women who received antepartum/intrapartum ARVs but with suboptimal viral suppression near delivery: 6 weeks of neonatal AZT chemoprophylaxis Consider multidrug prophylaxis, though no data address whether 2-3 drug infant regimen is more effective in this scenario Scheduled C-section is recommended if women have VL >1,000 copies/ml near time of delivery. March 2014

Infants born to mothers who received only intrapartum ARV drugs (AI): Standard 6-week course of AZT, plus 3 doses of NVP in the first week of life 1st dose at birth 2nd dose 48 hours later 3rd dose 96 hours after 2nd dose Begin regimen as soon as possible postdelivery March 2014

Infants born to women who did not receive antepartum or intrapartum ARVs: Standard 6-week course of AZT, plus 3 doses of NVP in the first week of life, as above Begin regimen as soon as possible postdelivery March 2014

Infants born to mothers with unknown HIV status: Do expedited (rapid) HIV testing of mothers and/or infants as soon as possible (during labor or after birth) If initial test result is positive: Initiate infant ARV prophylaxis immediately (AII) Do not wait for confirmatory testing Send confirmatory test (mother or infant) If negative, stop infant ARV prophylaxis (AIII) If positive, perform an HIV nucleic amplification test on the infant (AIII) March 2014

Infants born to mothers with ARV-resistant virus: Optimal prophylactic regimen for newborns is unknown Consult with a pediatric HIV specialist before delivery Standard 6-week course of AZT is recommended; consider addition of other ARVs selected on basis of mother’s virus resistance testing March 2014

Short-Term ARV Safety in Neonatal Prophylaxis
AZT: transient hematologic toxicity (mainly anemia) 3TC: in combination with AZT may cause more severe anemia and neutropenia TDF and FTC: limited data and safety; not recommended for infant prophylaxis NVP: no cases of severe rash or hepatotoxicity with neonatal prophylaxis Resistance may occur in infants who become infected despite prophylaxis PIs: not recommended for infant prophylaxis during the first few weeks of life; no PK and safety data RAL: not recommended; no PK and safety data available March 2014

Infant Antiretroviral Drugs – Premature Infants
The use of ARV drugs other than AZT and NVP is not recommended for premature infants in the United States. (BIII) A decision to combine other drugs with AZT regimen should be made in consultation with a pediatric HIV specialist. (BIII) March 2014

Infant Antiretroviral Management: Consultation
Clinician Consultation Center (formerly the National Perinatal HIV Hotline), : free clinical consultation on perinatal HIV March 2014

Initial Postnatal Management of the HIV-Exposed Neonate (1)
Obtain a CBC with differential before initiation of ARV prophylaxis. (BIII) Frequency of monitoring blood levels is based on: (CIII) Gestational age and clinical condition of infant Baseline values ZDV dosage administered Receipt of other ARV drugs Concomitant medications Maternal ARV regimen March 2014

Consider more frequent monitoring for infants exposed to combination ARV regimes in utero or neonatally: (CIII) CBC Serum chemistry Liver function Bilirubin levels (ATV exposure) March 2014

For infants receiving combination ZDV/3TC-containing ARV prophylaxis: (AI) Recheck hemoglobin and neutrophil count 4 weeks after ARV initiation and/or at the time HIV diagnostic testing is performed. March 2014

If hematological abnormalities are identified, considerations about continuing ARV prophylaxis include: (CIII) Extent of abnormality Related symptoms Duration of prophylaxis Risk of HIV infection Availability of alternative interventions May consider reducing prophylaxis to 4 weeks ̶ consult a pediatric HIV specialist March 2014

Routine measurement of serum lactate is not recommended unless infant develops severe clinical symptoms of unknown etiology. (CIII) Especially neurologic symptoms In symptomatic infants with significantly abnormal serum lactate levels (>5 mmol/L): Discontinue ARV prophylaxis Consult a pediatric HIV specialist for alternative prophylaxis March 2014

Diagnosing HIV Infection in Infants (1)
Diagnostic HIV tests for infants: (AII) Use HIV nucleic amplification testing (eg, HIV DNA and RNA PCR and related assays) Maternal HIV antibodies cross placenta and are detectable in HIV-exposed infants for up to 18 months Standard antibody tests cannot be used to diagnose HIV infection in infants March 2014

Virologic tests should be performed at: (AII) 14-21 days, 1-2 months, and 4-6 months Virologic test may be performed at birth: If mother did not have good virologic control during pregnancy, or If adequate follow-up cannot be assured Confirm a positive HIV virologic test with a second virologic test on a different specimen March 2014

HIV infection in an infant is diagnosed by 2 positive virologic tests on separate specimens HIV DNA (rather than RNA) may be optimal for HIV diagnosis in neonatal period March 2014

HIV infection is excluded: Presumptively by 2 negative virologic tests, 1 at age ≥14 days and 1 at age ≥1 month Definitively (in non-breast-fed infants) by 2 negative virologic tests, 1 at age ≥1 month or older and 1 at age ≥4 months Many experts confirm negative status by antibody testing at months (HIV antibodies can sometimes occur at or beyond 18 months) Diagnosis of non-subtype-B HIV may be difficult: see Guidelines March 2014

Postnatal Management of the HIV-Exposed Neonate: Prophylaxis and Immunizations
PCP prophylaxis should begin at age 4-6 weeks, after completion of ARV prophylaxis. (AII) Unless HIV infection can be presumptively excluded Evaluate and treat infants as indicated for transmittable maternal coinfection identified through history or physical evaluation HIV-exposed infants should follow the routine immunization schedule March 2014

Infant Feeding Practices and Risk of HIV Transmission
To prevent HIV transmission to infants in the United States: HIV-infected women should not breast-feed ART may decrease free HIV virus in breast milk, but cell-associated virus remains and may pose transmission risk Feeding with premasticated foods may transmit HIV Health providers should: (AII) Inquire about premastication and instruct HIV-infected caregivers to avoid the practice Advise on safer feeding options March 2014

Long-Term Follow-Up of Infants Exposed to ARVs
Long-term data from infants exposed to ARVs in utero are insufficient. Children with in utero or neonatal exposure to ARVs who develop significant organ system abnormalities of unknown etiology, particularly the nervous system or heart, should be evaluated for mitochondrial dysfunction. (CIII) Follow-up of children with exposure should continue to adulthood because of theoretical concerns for carcinogenicity of nucleoside analogues. (CIII) March 2014

LESSONS LEARNED FROM CLINICAL TRIALS OF ANTIRETROVIRAL INTERVENTIONS TO REDUCE PERINATAL TRANSMISSION OF HIV

Overview Pediatric AIDS Clinical Trials Group 076
Major achievement in HIV research Showed administration of zidovudine (ZDV) to pregnant women and their infants could reduce perinatal transmission by 70% Increased HIV testing in pregnancy and combination ARV prophylaxis during pregnancy has reduced perinatal transmission in the United States to <2% Every HIV-infected infant is a sentinel event representing missed opportunities March 2014

ARV Prophylaxis: Mechanisms of Action
Combined antepartum, intrapartum, and infant ARV prophylaxis is recommended to prevent perinatal transmission of HIV. (AI) ARV drugs reduce perinatal transmission by several mechanisms, including: Lowering maternal antepartum VL Providing infant pre- and postexposure prophylaxis March 2014

ARV Prophylaxis: Summary
Combination antenatal prophylaxis taken over longer duration is more effective then a short-course, single-drug regimen in reducing perinatal transmission. Combination infant ARV prophylaxis is recommended in the United States for infants whose mothers have not received antenatal ARV drugs. Adding single-dose intrapartum NVP is not recommended for women in the United States who are receiving standard recommended antenatal ARV prophylaxis. Breast-feeding by HIV-infected mothers is not recommended in the United States. March 2014

ARV Pregnancy Registry
To report cases of HIV-infected pregnant women and their newborns of prenatal exposure to ARVs for the purpose of assessing its potential teratogenicity contact: ARV Pregnancy Registry Research Park 1011 Ashes Drive Wilmington, NC 28405 (T) (F) March 2014

Websites to Access the Guidelines
March 2014

Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission.

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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.

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Presentation on theme: "Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission."— Presentation transcript:

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