Resource-Limited Settings

Discussion

Epidemiology of Mother-to-Child Transmission (MTCT) in Resource-Limited Settings

In 2011, there were an estimated 330,000 new pediatric HIV infections globally, approximately half the number of new pediatric HIV infections recorded in 2003 (Figure 1) [1]. This remarkable progress in reducing HIV incidence among children can be attributed primarily to widespread implementation of universal HIV screening policies for pregnant women and improved linkage to prevention of mother-to-child transmission (PMTCT) services. In 2011, 57% of pregnant women with HIV in low- and middle-income countries received effective antiretroviral drugs to prevent HIV transmission to their child (Figure 2), continuing a trend of improved access to PMTCT [1].

Timing of Perinatal HIV Infection

Transmission of HIV from a mother to her infant can occur in utero, during delivery, and by breastfeeding (Figure 3)[2]. Among breastfeeding populations with no antiretroviral therapy given, the risk of mother-to-child transmission of HIV is approximately 20 to 45% [3]. Maternal HIV RNA level is the strongest predictor of HIV transmission in utero [4]. Co-infections, such as herpes simplex virus, malaria, tuberculosis, and syphilis, have also been associated with increased risks of antepartum HIV transmission[2,5].

Antenatal PMTCT Options in Resource-Limited Settings

The WHO recommends that countries adopt one of three approaches (Option “A”, “B”, or “B+”) for managing HIV-infected pregnant women (Figure 4)[6]. For pregnant HIV-infected women who meet clinical and/or immunologic criteria for receipt of antiretroviral therapy (such as WHO stage III or IV disease, or an absolute CD4 count less than 350 cells/mm³), all three options endorse immediate initiation of triple antiretroviral therapy for the mother. The options differ with respect to management of the pregnant woman who does not meet criteria to receive antiretroviral therapy for her own health:

• Option A. Zidovudine monotherapy started at 14 weeks gestation (or as soon as possible thereafter), followed by single-dose nevirapine and initiation of zidovudine-lamivudine combination therapy at onset of labor. A ‘tail’ of zidovudine-lamivudine is continued for one week postpartum in order to reduce the risk of HIV developing resistance to nevirapine. The single-dose nevirapine and zidovudine-lamivudine tail can be omitted if the mother received at least four weeks of zidovudine monotherapy prior to delivery.
• Option B. Triple antiretroviral therapy started at 14 weeks gestation (or as soon as possible thereafter), continued throughout labor and delivery and continuing until one week after cessation of breastfeeding, at which time antiretroviral therapy for the mother is discontinued.
• Option B+. Triple antiretroviral therapy started as soon as HIV infection is diagnosed (or as soon as possible thereafter), continued throughout labor and delivery and indefinitely postpartum.

In each scenario, the infant receives daily nevirapine antiretroviral prophylaxis following delivery (Figure 4)[6]. Women and infants who did not receive antiretrovirals prior to labor and delivery follow separate guidelines.

Comparison of Options

When implemented properly, the three options listed above have roughly equal efficacy in preventing perinatal HIV transmission[3,6] but differ in cost and operational complexity. The 2010 PMTCT Guidelines issued by the WHO recommended that countries adopt either Option A or Option B depending upon local circumstances. In contrast, some countries, such as Malawi, adopted a variation, Option B+, in which triple antiretroviral therapy is started for all pregnant women and continued for life following labor and delivery. The success of this approach in Malawi prompted the WHO to release an update to its PMTCT guidelines in 2012 that promoted Option B+ based on its operational simplicity and other advantages (Figure 5)[6] . The WHO now recommends all three options as reasonable choices for national PMTCT programs while highlighting the relative advantages of the B+ approach.

Choice of Antiretroviral Treatment Approach during Pregnancy

The selection of the PMTCT regimen for a pregnant woman will depend on her health and which option (A, B, or B+) is being implemented in her country (Figure 4)[6].

• Zidovudine Monotherapy: This PMTCT treatment approach is indicated only for women who are living in countries where Option A has been adopted and who do not meet criteria for antiretroviral therapy for their own health (if CD4 count testing is not readily available for a pregnant woman in an Option A country, it may be preferable to initiate triple antiretroviral therapy instead of zidovudine monotherapy). Zidovudine dosed at 300 mg twice daily is started at 14 weeks gestational age (or as soon as possible thereafter) and continued throughout pregnancy. A single 200 mg dose of nevirapine is administered at the start of labor to further reduce the risk of HIV transmission during delivery. In order to reduce the likelihood that the mother’s strain of HIV will develop resistance to nevirapine, oral zidovudine plus lamivudine should also be started during labor and continued for seven days postpartum. If, however, the mother received more than four weeks of zidovudine monotherapy prior to the onset of labor, the single-dose nevirapine and seven day zidovudine/lamivudine ‘tail’ may be omitted; in this scenario, oral zidovudine dosed at 300 mg twice daily is continued throughout labor and discontinued after delivery.
• Triple Antiretroviral Therapy: Triple antiretroviral therapy is indicated for pregnant women who need HAART for their own health, and for all pregnant women living in countries in which the Option B or B+ approach is implemented. Recommended triple antiretroviral therapy regimens for most pregnant women in resource-limited settings now align with guidelines for non-pregnant adults and adolescents, consisting of two nucleoside reverse-transcriptase inhibitors (NRTIs) paired with a non-nucleoside reverse-transcriptase inhibitor (NNRTI) (Figure 6)[3].  For most pregnant women, a fixed-dose combination of tenofovir plus lamivudine (or emtricitabine) plus efavirenz will be the most appropriate antiretroviral option, given the efficacy, convenience, and low toxicity profile of this regimen.  Alternative regimens may be indicated for women with compromised renal function or prior exposure to PMTCT regimens, as described below.
• Use of Efavirenz in Pregnancy: In 2012, the WHO included efavirenz in the recommended first-line antiretroviral triple drug regimens for all, including pregnant women and non-pregnant women who may become pregnant[7]. Although concerns exist regarding possible teratogenicity of efavirenz, an accumulation of clinical experience with efavirenz in pregnancy has not documented an increase in the rates of birth defects among infants born to women taking this drug.[8,9]. In addition, clinical trials data suggest that efavirenz-based regimens are associated with less toxicity and better long-term outcomes for mothers as compared with nevirapine-based regimens (Figure 7) [7,10,11,12]. Finally, the cost of efavirenz has declined dramatically (Figure 8), and efavirenz is now available in convenient once-daily fixed dose combination tablets, co-formulated with tenofovir and either lamivudine or emtricitabine[7]. For all of these reasons, the WHO now recommends that unless specifically contraindicated, pregnant women should receive efavirenz-based antiretroviral therapy regimens[7].
• Use of Nevirapine in Pregnancy: Nevirapine remains an option for inclusion in first-line antiretroviral therapy regimens for pregnant women, but the WHO does not recommend this agent for women with CD4 counts greater than 350 cells/mm³ due to an increased incidence of severe nevirapine-related toxicity in women with high CD4 counts[13,14]. Data are conflicting and limited regarding the risk of hepatic toxicity in women with CD4 counts between 250 and 350 cells/mm³.  Accordingly, the WHO guidelines recommend close clinical monitoring (and laboratory monitoring, if feasible) during the first 12 weeks of therapy, particularly when NVP is initiated in women with CD4 counts of 250 to 350 cells/mm³. To decrease toxicity, reduced lead-in dosing (200 mg once daily) is recommended for the first 2 weeks when starting NVP[3].
• Use of Tenofovir in Pregnancy: Although there is more experience with the use of zidovudine in pregnancy, tenofovir offers important advantages over zidovudine in that it is generally better tolerated and is available in a once-daily, fixed-dose combination pill paired with efavirenz and lamivudine (or emtricitabine). Safety data regarding the use of tenofovir in pregnancy have been reassuring to date, failing to identify any increased risk of fetal or maternal complications[15,16]. Tenofovir should be avoided in pregnant women with renal disease
• Use of Zidovudine in Pregnancy: Zidovudine has an extensive record of safety and efficacy in pregnancy and is widely used for PMTCT. Zidovudine is equivalent to tenofovir, but it requires twice-daily dosing. Zidovudine should be used in pregnant women with renal disease or other contraindications to tenofovir. Zidovudine should be avoided in pregnant women with moderate or severe anemia (defined as a hemoglobin level less than 8 mg/dL).
• Emtricitabine (FTC) versus Lamivudine (3TC): These two agents are virtually identical in terms of safety profile, efficacy, and resistance considerations. The decision regarding which one to use will typically depend upon which one is included in locally available fixed-dose combinations of antiretrovirals.
• Regimens for Women with Prior Exposure to PMTCT Prophylaxis: Substitution of a ritonavir-boosted protease inhibitor (such as lopinavir-ritonavir) for the NNRTI component is recommended for women who received single-dose nevirapine without an NRTI ‘tail’ within the past twelve months (Figure 9)[3]. Mothers who receive intrapartum single-dose nevirapine, alone or with antepartum zidovudine, may acquire resistance to non-nucleoside reverse transcriptase inhibitor drugs due to the long serum half-life of nevirapine. Administration of additional antiretrovirals for one week (typically zidovudine plus lamivudine) immediately after single-dose nevirapine significantly reduces the risk of developing NNRTI resistance[17,18,19], and mothers who receive this one-week ‘tail’ of zidovudine plus lamivudine after single-dose nevirapine may be prescribed NNRTI-based triple antiretroviral therapy in subsequent pregnancies, though checking a viral load six months into therapy is recommended in this scenario (Figure 9)[3].  NNRTI-based triple antiretroviral therapy may also be prescribed to pregnant women who received single-dose nevirapine, with or without a tail, more than one year prior to their current pregnancy, because the risk of NNRTI resistance wanes with time[20,21,22,23,24,25].