Antiretroviral Clinical Scenarios

Scenario #1: HIV-Infected Pregnant Women Who Have Not Received Prior Antiretroviral Therapy

Recommendation
Pregnant women with HIV infection must receive standard clinical, immunologic, and virologic evaluation. Recommendations for initiation and choice of antiretroviral therapy should be based on the same parameters used for persons who are not pregnant, although the known and unknown risks and benefits of such therapy during pregnancy must be considered and discussed (14). The three-part ZDV chemoprophylaxis regimen, initiated after the first trimester, should be recommended for all pregnant women with HIV infection regardless of antenatal HIV RNA copy number to reduce the risk for perinatal transmission. The combination of ZDV chemoprophylaxis with additional antiretroviral drugs for treatment of HIV infection is recommended for infected women whose clinical, immunologic or virologic status requires treatment or who have HIV RNA over 1,000 copies/mL regardless of clinical or immunologic status. Women who are in the first trimester of pregnancy may consider delaying initiation of therapy until after 10-12 weeks' gestation.

Discussion

When ZDV is administered in the three-part PACTG 07 regimen, perinatal transmission is reduced by approximately 70%. The mechanism by which ZDV reduces transmission is not known. However, protection is likely multifactorial. Pre-exposure prophylaxis of the infant is provided by passage of ZDV across the placenta. Thus, inhibitory levels of the drug are present in the fetus during the birth process. While placental passage of ZDV is excellent, other antiretroviral drugs have variable transplacental passage (Table 2). Therefore, when combination antiretroviral therapy is initiated during pregnancy, ZDV should be included as a component of antenatal therapy whenever possible. Since the mechanism by which ZDV reduces transmission is not known, the intrapartum and newborn ZDV parts of the chemoprophylactic regimen should be administered to reduce perinatal HIV transmission. If a woman does not receive ZDV as a component of her antenatal antiretroviral regimen, intrapartum and newborn ZDV should continue to be recommended.

Women should be counseled that potent combination antiretroviral regimens have substantial benefit for their own health and may provide enhanced protection against perinatal transmission. Several studies have indicated that women with low or undetectable HIV-1 RNA levels (e.g. <1,000 copies/mL) have extremely low rates of perinatal transmission, particularly when antiretroviral therapy has been received (70, 71, 81). However, there is no threshold below which lack of transmission can be assured, and the long-term effects of in utero exposure to multiple antiretroviral drugs is unknown. Decisions regarding the use and choice of an antiretroviral regimen should be individualized based on discussion with the woman about a) her risk for disease progression and the risks and benefits of delaying initiation of therapy; b) possible benefit of lowering viral load for reducing perinatal transmission; c) potential drug toxicities and interactions with other drugs; d) the need for strict adherence to the prescribed drug schedule to avoid the development of drug resistance; e) unknown long-term effects of in utero drug exposure on the infant; and f) pre-clinical, animal, and clinical data relevant to use of the currently available antiretrovirals during pregnancy. Due to the evolving and complex nature of the management of HIV-1 infection, a specialist with experience in the treatment of pregnant women with HIV infection should be involved in their care.

Because the period of organogenesis (when the fetus is most susceptible to potential teratogenic effects of drugs) is during the first 10 weeks of gestation and the risks of antiretroviral therapy during that period are unknown, women who are in the first trimester of pregnancy may wish to consider delaying initiation of therapy until after 10-12 weeks' gestation. This decision should be carefully considered and discussed between the health-care provider and the patient; such a discussion should include an assessment of the woman's health status and the benefits and risks of delaying initiation of therapy for several weeks, and the knowledge that most perinatal HIV-1 transmission likely occurs late in pregnancy or during delivery. Treatment with efavirenz should be avoided during the first trimester because significant teratogenic effects in rhesus macaques were seen at drug exposures similar to those representing human exposure. Hydroxyurea is a potent teratogen in a variety of animal species and should also be avoided during the first trimester (Table 2 and see **SAFETY AND TOXICITY OF INDIVIDUAL ANTIRETROVIRAL DRUGS IN PREGNANCY **).

When initiation of antiretroviral therapy would be considered optional based on current guidelines for treatment of non-pregnant individuals (14), infected pregnant women should be counseled regarding the potential benefits of standard combination therapy and should be offered such therapy, including the three-part ZDV chemoprophylaxis regimen. Although such women are at low risk for clinical disease progression if combination therapy is delayed, antiretroviral therapy that successfully reduces HIV-1 RNA to levels below 1,000 copies/mL may substantially lower the risk of perinatal HIV-1 transmission and limit consideration of elective cesarean delivery as an intervention to reduce transmission risk.

When combination therapy is administered, the regimen should be chosen from those recommended for non-pregnant adults (14). Dual nucleoside analogue therapy without the addition of either a protease inhibitor or non-nucleoside reverse transcriptase inhibitor is not recommended due to the potential for inadequate viral suppression and rapid development of resistance (99). If combination therapy is given principally to reduce perinatal transmission and would have been optional for treatment of non-pregnant individuals, consideration may be given to discontinuing therapy postnatally, with the decision to reinitiate treatment based on standard criteria for non-pregnant individuals. If drugs are discontinued postnatally, all drugs should be stopped simultaneously. Discussion regarding the decision to continue or stop combination therapy postpartum should occur prior to initiation of therapy during pregnancy.

Use of antiretroviral prophylaxis has been shown to provide benefit in preventing perinatal transmission even for infected pregnant women with HIV-1 RNA levels < 1,000 copies/mL. In a meta-analysis of factors associated with perinatal transmission among women who had infected infants despite having HIV-1 RNA <1,000 copies/mL at or near delivery, transmission was only 1.0% among women receiving antenatal antiretroviral therapy (primarily ZDV alone) compared to 9.8% among those receiving no antenatal therapy (100). Therefore, use of antiretroviral prophylaxis is recommended for all pregnant women with HIV infection regardless of antenatal HIV RNA level.

The time-limited use of ZDV alone during pregnancy for chemoprophylaxis of perinatal transmission is controversial. The potential benefits of standard combination antiretroviral regimens for treatment of HIV infection should be discussed with and offered to all pregnant women with HIV infection regardless of viral load, and is recommended for all pregnant women with HIV-1 RNA levels >1,000 copies/mL. However, some women may wish to restrict exposure of their fetus to antiretroviral drugs during pregnancy but still wish to reduce the risk of transmitting HIV to their infant. Additionally, for women with HIV-1 RNA levels <1,000 copies/mL, time-limited use of ZDV during the second and third trimesters of pregnancy is less likely to induce the development of resistance due to the limited viral replication existing in the patient and the time-limited exposure to the antiretroviral drug. For example, the development of ZDV resistance was unusual among the healthy population of women who participated in PACTG 076 (52). The use of ZDV chemoprophylaxis alone during pregnancy might be an appropriate option for these women.

See Table 3: Clinical Scenarios and Recommendations for the Use of Antiretroviral Drugs to Reduce Periantal Human Immunodeficiency Virus (HIV) Transmission

Scenario #2: HIV-Infected Women Receiving Antiretroviral Therapy During the Current Pregnancy

Recommendation
HIV-1 infected women receiving antiretroviral therapy in whom pregnancy is identified after the first trimester should continue therapy. ZDV should be a component of the antenatal antiretroviral treatment regimen after the first trimester whenever possible, although this may not always be feasible. For women receiving such therapy in whom pregnancy is recognized during the first trimester, the woman should be counseled regarding the benefits and potential risks of antiretroviral administration during this period, and continuation of therapy should be considered. If therapy is discontinued during the first trimester, all drugs should be stopped and reintroduced simultaneously to avoid the development of drug resistance. Regardless of the antepartum antiretroviral regimen, ZDV administration is recommended during the intrapartum period and for the newborn. Recommendations for resistance testing in HIV-infected pregnant women are the same as for non-pregnant patients: acute HIV infection and virologic failure or suboptimal viral suppression after initiation of antiretroviral therapy.

Discussion
Women who have been receiving antiretroviral treatment for their HIV infection should continue treatment during pregnancy. Discontinuation of therapy could lead to an increase in viral load, which could result in decline in immune status and disease progression and result in adverse consequences for both the fetus and the woman.

ZDV should be a component of the antenatal antiretroviral treatment whenever possible. However, there may be circumstances where this is not feasible, such as the occurrence of significant ZDV-related toxicity. Additionally, women receiving an antiretroviral regimen that does not contain ZDV but who have HIV-1 RNA levels that are consistently very low or undetectable (e.g., <1,000 copies/mL) have a very low risk of perinatal transmission (81), and there may be concerns that the addition of ZDV to the current regimen could compromise adherence to treatment.

The maternal antenatal antiretroviral treatment regimen should be continued on schedule as much as possible during labor to provide maximal virologic effect and to minimize the chance of development of drug resistance. If a woman has not received ZDV as a component of her antenatal therapeutic antiretroviral regimen, intravenous ZDV should still be administered to the pregnant woman during the intrapartum period whenever feasible. Because ZDV and d4T should not be administered together due to potential pharmacologic antagonsim, options for women receiving oral d4T as part of their antenatal therapy include continuation of oral d4T during labor without intravenous ZDV, or withholding oral d4T during the period of intravenous ZDV administration during labor. Additionally, the infant should receive the standard 6 week course of ZDV.

For women with suboptimal suppression of HIV-1 RNA (e.g., above 1,000 copies/mL) near the time of delivery despite prenatal receipt of ZDV prophylaxis and/or combination antiretroviral therapy, there are currently no data to demonstrate that administration of additional antiretroviral drugs during labor and delivery provides added protection against perinatal transmission. In the HIVNET 012 study in Ugandan women without antenatal antiretroviral therapy, a two-dose nevirapine regimen (single dose to the woman at the onset of labor and single dose to the infant at age 48 hours) significantly reduced perinatal transmission compared to a ultra-short intrapartum/1 week postpartum ZDV regimen (61). In women in the United States, Europe, Brazil and the Bahamas who are receiving antenatal antiretroviral therapy, PACTG 316 is evaluating the addition of the same two-dose intrapartum/postpartum nevirapine regimen to standard therapy compared to the addition of a nevirapine placebo. Final results of PACTG 316 are anticipated in early 2001, but due to an unexpectedly low overall transmission rate, the study will have limited power to address whether nevirapine provides any additional benefit for reducing transmission in women who have received antenatal therapy.

Selection of nevirapine-resistant virus was found at 6 weeks postpartum in pregnant women receiving a single dose of nevirapine during labor. In HIVNET 012, where drugs other than nevirapine were not given, 7 of 31 women (23%) evaluated.developed genotypic resistance mutations at 6 weeks postpartum; these mutations were no longer present in 4 women studied at 13-18 months postpartum (105, 106). In the antiretroviral-treated women in PACTG 316, 4 of 32 women (13%, 95% CI 4-25%) with HIV-1 RNA above 3,000 copies/mL at delivery who received nevirapine developed genotypic nevirapine resistance mutations compared to none of 38 women in the placebo arm (107).

The duration that nevirapine-resistant mutations persist following the removal of the selective pressure induced by the single dose of nevirapine in women with and without antenatal antiretroviral treatment remains unclear. The clinical implications of these findings for future maternal treatment options, especially among women with access to standard combination antiretroviral therapies, remain unknown at present. If the addition of the two-dose nevirapine regimen to existing antiretroviral therapy is considered for a woman currently receiving treatment, the potential implications for future maternal therapy and the unproven benefit in further reducing transmission need to be weighed very carefully and discussed with the woman. Guidelines on decisions related to obstetric interventions to reduce perinatal transmission in antiretroviral-treated women with suboptimal virologic suppression near the time of delivery are outlined in the "Perinatal HIV-1 Transmission and Mode of Delivery" section of this document.

The impact of prior antiretroviral exposure on the efficacy of ZDV chemoprophylaxis is unclear. Data from PACTG 185 indicate that duration of prior ZDV therapy in women with advanced HIV-1 disease, many of whom received prolonged ZDV before pregnancy, was not associated with diminished ZDV efficacy for reduction of transmission (57). Perinatal transmission rates were similar for women who first initiated ZDV during pregnancy and women who had received ZDV prior to pregnancy. Thus, a history of ZDV therapy before the current pregnancy should not limit recommendations for administration of ZDV chemoprophylaxis to reduce perinatal HIV-1 transmission.

Some clinicians have recommended antiretroviral drug resistance testing for all pregnant women, although this is controversial (108). Although perinatal transmission of ZDV-resistant virus has been reported, it is unclear if the presence of genotypic drug resistance mutations increase the risk of transmission, and the utility of resistance testing in pregnant women receiving antitretroviral treatment who have successful virologic control is minimal. In PACTG 076, the prevalence and incidence of ZDV resistance was low (3%) and the presence of resistance did not correlate with transmission (52). However, in a cohort of women with more advanced disease who were receiving antenatal monotherapy with ZDV between 1989-1994 (prior to the results of.January 24, 2001 PACTG 076), the prevalence of ZDV resistance was 24%; in multivariate analysis, the presence of ZDV drug resistance was associated with perinatal transmission (109). Drug-resistant virus may have decreased fitness in terms of perinatal transmission; in a study of the preceding cohort of women that evaluated transmitting mother/infant pairs, only wild-type virus was transmitted to infected infants born to infected women with mixed populations of wild type and low level ZDV resistant virus (110). In a Swiss study in of 62 HIV-infected women, 10% had virus with high level ZDV resistance, but none of the women transmitted HIV-1 to their infant despite receiving only ZDV prophylaxis (111). Antiretroviral resistance testing is expensive, difficult to interpret, and data to support its routine use in pregnancy outside of standard indications in non-pregnant individuals is currently lacking. Further, if a woman’s therapeutic regimen is successful (e.g., HIV-1RNA is reduced to <1,000 copies/mL) it both suggests that resistance has not occurred and that transmission will be very unlikely regardless of the results of resistance testing. Therefore, at present, recommendations for resistance testing in HIV-infected pregnant women are the same as for non-pregnant patients: acute HIV infection and virologic failure or suboptimal viral suppression after initiation of antiretroviral therapy (14).

Some women receiving antiretroviral therapy may realize they are pregnant early in gestation, and concern for potential teratogenicity may lead some to consider temporarily stopping antiretroviral treatment until after the first trimester. Data are insufficient to support or refute the teratogenic risk of antiretroviral drugs when administered during the first 10 weeks of gestation; certain drugs are more of concern than others. (Table 2 and see **SAFETY AND TOXICITY OF INDIVIDUAL ANTIRETROVIRAL DRUGS IN PREGNANCY **). The decision to continue therapy during the first trimester should be carefully considered and discussed between the clinician and the pregnant woman. Such considerations include gestational age of the fetus; the woman's clinical, immunologic, and virologic status; and the known and unknown potential effects of the antiretroviral drugs on the fetus. If antiretroviral therapy is discontinued during the first trimester, all agents should be stopped and restarted simultaneously in the second trimester to avoid the development of drug resistance. No data are available to address whether transient discontinuation of therapy is harmful for the woman and/or fetus.

Some health-care providers might consider administration of ZDV in combination with other antiretroviral drugs to newborns of women with a history of prior antiretroviral therapy— particularly in situations where the woman is infected with HIV-1 with documented high-level ZDV resistance, has had disease progression while receiving ZDV, or has had extensive prior ZDV monotherapy. However, the efficacy of this approach is not known. The appropriate dose and short- and long-term safety for most antiretroviral agents other than ZDV are not defined for neonates. The half-lives of ZDV, 3TC, and nevirapine are prolonged during the neonatal period as a result of immature liver metabolism and renal function, requiring specific dosing adjustments when these antiretrovirals are administered to neonates. Data regarding the pharmacokinetics of other antiretroviral drugs in neonates are not yet available, although phase I neonatal studies of several other antiretrovirals are ongoing. The infected woman should be counseled regarding the theoretical benefit of combination antiretroviral drugs for the neonate, the potential risks, and what is known about appropriate dosing of the drugs in newborn infants. She should also be informed that use of antiretroviral drugs in addition to ZDV for newborn prophylaxis is of unknown efficacy for reducing risk for perinatal transmission.

See Table 3: Clinical Scenarios and Recommendations for the Use of Antiretroviral Drugs to Reduce Periantal Human Immunodeficiency Virus (HIV) Transmission

Scenario #3: HIV-Infected Women in Labor Who Have Had No Prior Therapy