International recommendations on antiretroviral drugs for treatment of HIV-infected women and prevention of mother-to-child HIV transmission in resource-limited settings: 2006 update

Article Outline

• Abstract
• Clinical Trials of Antiretroviral Prophylaxis of MTCT: Lessons Learned
  • Combination antiretroviral regimens are more effective than single-drug antiretroviral regimens
  • Longer duration of antiretroviral prophylaxis is more effective
  • Efficacy of antiretroviral regimens is diminished over time in breastfeeding populations
  • Addition of SD-NVP improves the efficacy of other short-course antiretroviral regimens
  • Relative importance of maternal vs infant SD-NVP is unclear
  • Short-course combination antiretroviral regimens are as effective as HAART for the reduction of MTCT in pregnant women who do not require treatment for their own health
  • SD-NVP and NVP resistance
• WHO Recommendations for the Use of ART for Maternal Treatment and Prevention of MTCT
  • HIV-infected women who require ART for their own health
    • When to start HAART
    • First-line regimen
  • HIV-infected pregnant women whose condition does not require ART or where ART is not available: antiretroviral prophylaxis for PMTCT
    • HIV-infected women who are seen during pregnancy (Tables 2 and 3)
    • HIV-infected women who are in labor and who have not received antiretroviral prophylaxis (Tables 2 and 4)
  • Infants who are born to HIV-infected women who have not received antiretroviral drugs during pregnancy or labor (Tables 2 and 5)
  • HIV-infected women who are breastfeeding
• Comment
• Acknowledgment
• References
• Copyright

The World Health Organization recommends that countries adopt more effective antiretroviral regimens to increase the effectiveness of the prevention of mother-to-child human immunodeficiency virus (HIV) transmission programs. The 2006 guidelines recommend a tiered approach for the delivery of antiretroviral to pregnant women who are infected with HIV and include triple-drug antiretroviral treatment for those women who are eligible. Those women who are not eligible for antiretroviral treatment should receive a combination prophylaxis antiretroviral regimen, preferably zidovudine from 28 weeks of gestation; zidovudine, lamivudine, and a single dose of nevirapine during delivery; and zidovudine and lamivudine for 7 days after delivery to reduce the development of nevirapine resistance. Newborn infants should receive a single dose of nevirapine and 1-4 weeks of zidovudine, depending on the duration of the regimen received by the mother. Although steps are being taken to provide more effective regimens, the use of single-dose nevirapine alone should still be used in situations in which more effective regimens are not yet feasible or available. HIV transmission through breastfeeding remains a problem, and several interventions are under evaluation that include maternal and/or infant antiretroviral prophylaxis during breastfeeding.

Key words: antiretroviral, HIV, prevention of mother-to-child transmission

The primary mode of acquisition of the human immunodeficiency virus (HIV) in children worldwide is through mother-to-child transmission (MTCT), which can occur during pregnancy, labor and delivery, or breastfeeding. Without interventions to reduce MTCT, the estimated risk of transmission ranges from 15%-25% in nonbreastfeeding populations and 25%-40% in breastfeeding populations.¹

In the last decade, there has been impressive success in the United States, Europe, and several other resource-rich countries in the reduction of MTCT. In 1994, the Pediatric AIDS Clinical Trials group (PACTG) protocol 076 showed that the administration of zidovudine (AZT) to the woman who is infected with HIV starting at approximately 14 weeks of gestation during pregnancy and labor and to her newborn infant decreased the risk of perinatal HIV transmission from 25.5% in the placebo arm to 8.3% in the AZT arm at 18 months, which is a relative risk reduction of nearly 70%.² With the implementation of recommendations for universal prenatal HIV testing and counseling, antiretroviral treatment (ART) and combination prophylaxis, elective cesarean delivery, and avoidance of breastfeeding, MTCT of HIV has decreased to <2% in resource-rich countries.³ Many antiretroviral drug regimens that are based on AZT, AZT and lamivudine (3TC), nevirapine (NVP), or combinations of these drugs that are used in highly active antiretroviral therapy (HAART) have been shown to reduce the MTCT of HIV.

In most resource-limited countries, especially in sub-Saharan Africa, national prevention of MTCT (PMTCT) programs are built around a regimen of single-dose NVP (SD-NVP) for women in labor and their newborn infants. From a public health standpoint, SD-NVP could be considered as a starting point and the minimum effective regimen in settings that currently do not have the capacity to deliver more effective combination regimens. Despite the wide use of simple regimens, the overall coverage of prevention of PMTCT programs and uptake of services that are provided through these programs is still very low worldwide. In 2006, worldwide, <10% of the estimated HIV-infected pregnant women received antiretroviral drugs for PMTCT of HIV.

This article presents a review of the key scientific evidence, progress, and lessons that have been learned in antiretroviral prophylaxis for MTCT and the new 2006 World Health Organization (WHO) public health guidelines for the treatment of pregnant women and the prevention of HIV infection in infants in resource-limited settings.⁴ Based on new evidence and programmatic experiences that have become available, the 2006 guidelines go beyond delivery of SD-NVP for PMTCT to the mother and the neonate to include more effective antiretroviral prophylaxis and treatment regimens. The new guidelines recommend a tiered approach for PMTCT antiretroviral interventions that supports the best interventions where feasible but at least some effective interventions at all levels of the health system. The guidelines recommend a public health approach that aims to support the development of PMTCT and treatment programs that can reach as many people as possible.⁵ This approach is built around evidence-based standardized regimens and simplification to facilitate the implementation at country level, balancing feasibility with impact, and flexibility to allow for changing circumstances. The guidelines complement and are harmonized fully with the WHO 2006 Adult⁶ and Pediatric HIV⁷ treatment guidelines.

The new guidelines differ from those in resource-rich settings primarily in recommendations for women who do not require antiretroviral therapy for their own health. In resource-rich settings, HAART is recommended for PMTCT in all pregnant women with HIV RNA levels of >1000 copies/mL and is often used in women with lower RNA levels.⁸ However, resource-limited settings have constraints that are related to cost, laboratory capacity, limited antiretroviral drugs that require the reserve of certain antiretrovirals for second-line and salvage therapy, and safety. With the public health approach to treatment, the first-line ART regimen for infected individuals in resource-limited settings, which includes women for whom contraception cannot be guaranteed, is a non–nucleoside reverse transcriptase inhibitor (NNRTI)–based regimen;⁶ in women, the NNRTI of choice is NVP. Protease inhibitors are reserved preferentially for second-line ART. However, there is the potential for life-threatening hepatic toxicity with chronic NVP therapy in women with higher CD4 cell counts. Thus, a new key point is that WHO recommends a 2-part approach for PMTCT in resource-limited settings: NVP-based ART for women whose condition requires therapy for their own health and short-course combination antiretroviral regimens plus single-dose intrapartum/neonatal SD-NVP for women who do not require therapy for their own health. Lessons learned from clinical trials and current WHO guidelines will be discussed later.

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Clinical Trials of Antiretroviral Prophylaxis of MTCT: Lessons Learned 

When first shown to be effective in 1994, the complexity and cost of the 3-part PACTG 076 AZT regimen limited its applicability and implementation in resource-limited settings, which led researchers to evaluate the efficacy of shorter, less expensive prophylactic regimens (Table 1). These studies demonstrate that a number of different regimens have efficacy in preventing in utero and intrapartum transmission, but that efficacy is diminished in breastfeeding populations because of postnatal HIV acquisition through breast milk.

TABLE 1. Results of major studies on antiretroviral prophylaxis to prevent mother-to-child HIV transmission⁴

Table 1 summarizes the results of the major clinical studies of antiretroviral interventions for PMTCT. Direct comparison between trials is difficult, because they enrolled patient populations from different geographic areas who were infected with different viral subtypes with different infant feeding practices and different infant age of diagnosis and outcome. However, some general conclusions can be drawn.

Combination antiretroviral regimens are more effective than single-drug antiretroviral regimens 

Efficacy has been demonstrated for regimens with AZT alone, AZT plus 3TC, SD-NVP, and more recently, SD-NVP plus either short-course AZT or AZT/3TC (Table 1).⁹, ¹⁰, ¹¹, ¹², ¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷, ¹⁸, ¹⁹, ²⁰ Combination regimens, such as short-course AZT plus SD-NVP, are more effective than single-drug regimens in reducing MTCT; when feasible and affordable, a longer 3-part antepartum/intrapartum/postpartum regimen is superior for PMTCT than a shorter 2-part antepartum/intrapartum or intrapartum/postpartum regimen.

Longer duration of antiretroviral prophylaxis is more effective 

Almost all studies in developing countries include an oral intrapartum antiretroviral prophylaxis component, with varying durations of maternal antiretroviral drug administration antepartum and postpartum and/or infant antiretroviral postpartum prophylaxis. Regimens with antepartum components that start as late as 36 weeks of gestation with no infant prophylaxis component can reduce the risk of transmission⁹, ¹¹; however, longer duration of antepartum therapy (starting at 28 weeks of gestation) is more effective than shorter duration regimens (starting at 36 weeks of gestation).¹⁰ Additionally, if the duration of the maternal antepartum regimen is short (<4 weeks), longer infant prophylaxis (4-6 weeks) appears more effective than shorter infant prophylaxis (3 days-1 week).¹¹

Regimens that include no antepartum prophylaxis but include intrapartum and postpartum drug administration are also effective, although less than those with an antepartum component.¹⁴, ¹⁵, ¹⁶ The WHO/UNAIDS multicenter trial to Prevent Mother to Child Transmission of HIV1 by short course ARV treatment (PETRA study) demonstrated that intrapartum prophylaxis with AZT/3TC alone, without postexposure prophylaxis of the infant, is not effective.¹⁴ The South African Nevirapine Trial (SAINT) demonstrated that the 2 proven effective intrapartum/postpartum regimens (AZT/3TC or SD-NVP) are similar in efficacy and safety.¹⁶

Efficacy of antiretroviral regimens is diminished over time in breastfeeding populations 

Although the short-course regimens that were identified as effective in nonbreastfeeding populations are also effective in breastfeeding populations, their efficacy in reducing antepartum and intrapartum transmission is overcome by subsequent risk from breastfeeding transmission.¹³, ¹⁴, ¹⁵ Efficacy was diminished subsequently (after 6 weeks) with AZT or AZT/3TC short-course regimens in 2 trials that followed infants to 18 months but was much less with SD-NVP in 1 trial. These differences may be explained partially by the prolonged half-life of NVP; detectable drug levels can persist for ≥2 weeks in women after SD-NVP,²¹ thereby providing a much longer period of prophylaxis then AZT and 3TC, which have significantly shorter half-lives. SD-NVP may protect uniquely against early breast milk HIV transmission, which is likely the highest risk time for breast milk transmission.²² In a study that compared the effect of SD-NVP to short-course AZT on breast milk HIV RNA levels, the SD-NVP regimen significantly reduced breast milk virus for approximately 2-3 weeks, but no reduction was seen with AZT.²³ Protection was also observed in a study in South Africa that compared SD-NVP with 6 weeks of AZT infant prophylaxis; AZT was significantly less effective in reducing MTCT in breastfeeding than formula-fed infants, whereas NVP was equally effective in reducing MTCT, regardless of infant feeding mode.²⁴

Addition of SD-NVP improves the efficacy of other short-course antiretroviral regimens 

To improve the efficacy of short-course regimens but to retain a simple low-cost approach, researchers have evaluated whether the addition of a potent intrapartum/postpartum intervention (the SD-NVP regimen) to short-course regimens might increase efficacy. The Perinatal HIV Prevention Trial (PHPT)-2 study in nonbreastfeeding women in Thailand and the “Diminution de la Transmission Mere-Enfant” (DITRAME) studies in a partly breastfeeding population in Côte d’ Ivoire demonstrated that the addition of SD-NVP to short-course AZT alone or to short-course AZT/3TC significantly increases efficacy (Table 1).¹⁷, ¹⁸, ²⁵, ²⁶ Data from Côte d’Ivoire indicate that short-course AZT plus SD-NVP has equivalent efficacy to short-course AZT/3TC plus SD-NVP.¹⁸ A clinical trial conducted in resource-rich countries, PACTG 316, demonstrated that the addition of SD-NVP did not appear to offer significant benefit in the setting of potent combination antiretroviral therapy throughout pregnancy and very low viral load at the time of delivery.²⁷

Relative importance of maternal vs infant SD-NVP is unclear 

The relative importance of maternal vs infant SD-NVP in the context of short-course AZT regimens remains unclear. The Thailand PHPT-2 study suggests that the infant SD-NVP dose at age 48 hours may not add significant efficacy to the maternal NVP dose alone. ¹⁷, ²⁵, ²⁶ Additionally, the Botswana Mashi study showed no difference in transmission rates between women who were given SD-NVP vs placebo in a setting in which women and infants received short-course AZT and infants received SD-NVP.¹⁷, ²⁵, ²⁶

In some countries, a significant proportion of women may lack antenatal care and first appear in the healthcare system in late labor, which is too late to allow the initiation of intrapartum prophylaxis. A Malawi trial in a breastfeeding population evaluated infant prophylaxis when no antepartum or intrapartum maternal ART was received. The addition of 1 week of AZT to infant SD-NVP reduced the risk of transmission by 36% in infants who were HIV-negative at birth, compared with infant SD-NVP alone, from 12.1% at 6-8 weeks in children with SD-NVP only to 7.7% in infants with SD-NVP plus AZT.¹⁹ However, when maternal intrapartum NVP was received, which provided preexposure prophylaxis in addition to postexposure prophylaxis, transmission rates at 6-8 weeks that excluded infections at birth were similar for infants who received SD-NVP only (6.5%) and for infants who received the combined NVP/AZT infant postexposure prophylaxis regimen (6.9%),²⁰ which suggests that NVP may have a unique impact on early postpartum transmission through breastfeeding.

Short-course combination antiretroviral regimens are as effective as HAART for the reduction of MTCT in pregnant women who do not require treatment for their own health 

A study in Côte d’Ivoire evaluated a 2-part PMTCT strategy of NVP-based HAART for women whose condition required therapy for their own health (eligible for treatment) and short-course AZT/3TC plus SD-NVP for women who were not eligible. Transmission in the women who received HAART was 2.4% (95% CI, 0.3%-8.5%), compared with 3.8% (95% CI, 1.0%-9.5%) in women who received the short-course combination regimen (P = .7).²⁸ Additionally, in a study in Mozambique where all women received NVP-based HAART regardless of indication, overall transmission was 2.7%, which was similar to that observed with the 2-part WHO-recommended approach in Côte d’Ivoire.²⁹

SD-NVP and NVP resistance 

NVP-prolonged half-life is beneficial in that NVP likely prevents postnatal MTCT during the first few weeks of life and intrapartum, but the prolonged presence of the single drug in the mother’s body also promotes the development of drug resistance. NVP drug resistance is well-known to develop in some women who receive either a single-dose or chronic therapy. The risk of NVP resistance after SD-NVP exposure is most strongly related to higher maternal plasma RNA levels and lower CD4 count at the time of exposure.³⁰ Other factors that are associated with the development of NVP resistance after MTCT prophylaxis include viral subtype (more common with subtype C and D than with subtype A), compartment (such as archived virus in breast milk or other organs), the number of NVP doses the woman receives during labor (repeat dosing induces more resistance), and the time since SD-NVP was received (resistance more likely closer to the time of exposure).³¹, ³²

NNRTI resistance can be detected within the first 6 months after SD-NVP with the use of standard genotyping in approximately 25%-50% of women who receive SD-NVP; however, more sensitive techniques have shown that NVP resistance may occur in as many as 60%-89% of women early after exposure.³³, ³⁴, ³⁵, ³⁶ The proportion of viral variants with NVP resistance declines over time, but low levels of resistant viral populations can be detected in some women for ≥1 year after exposure. The clinical significance of such low level resistance is unclear. NVP-resistant viral strains are also selected for women who received NVP in addition to other antiretroviral drugs for the prevention of MTCT, although rates may be lower than in for women who are exposed to SD-NVP alone.³⁷

The women who are most at risk of the development of NVP resistance with exposure to SD-NVP are those women with more advanced HIV disease. Therefore, 1 of the best ways to prevent the development of NVP resistance is likely to be the assessment of all pregnant women for their need for ART by clinical stage and CD4 count during pregnancy, if possible, and the initiation of HAART for those women who require therapy.³⁸

Some data suggest that the incidence of resistance may be decreased if a “tail” of other antiretroviral drugs is given during delivery and for a short period after delivery after SD-NVP.³⁹, ⁴⁰ However, the optimal antiretroviral regimen and duration are not yet known. The Treatment Option Preservation (TOPS) study in South Africa demonstrated that the administration of AZT/3TC during labor, in addition to SD-NVP, that is followed by AZT/3TC that is given for 4-7 days after delivery reduced the development of NVP resistance from 60%-10%.⁴⁰

Previous exposure to SD-NVP is not associated with increased risk of MTCT in subsequent pregnancies; studies in Côte d’Ivoire, South Africa, and Uganda have shown that previous exposure to SD-NVP did not reduce the efficacy of SD-NVP in subsequent pregnancies.⁴¹, ⁴²

The clinical consequences for mothers and children of NVP resistance in terms of response to future NNRTI-based HAART are under study. A Thailand study suggested that maximal viral suppression might be decreased in women who have received previous SD-NVP and later initiated NVP-based HAART, although clinical and immunologic responses did not differ from those without SD-NVP exposure.⁴³ The time between SD-NVP exposure and the initiation of NNRTI-based ART may be important. A lower rate of maximal viral suppression appears more likely if HAART is started at <6 months after SD-NVP exposure,⁴³ but recent studies from Botswana, South Africa, Côte d’Ivoire, and Zimbabwe suggest that virologic and immunologic response to therapy is the same as in women without SD-NVP exposure if HAART is started 6-18 months after exposure.⁴⁴, ⁴⁵, ⁴⁶, ⁴⁷ Studies are in progress to determine more definitively whether SD-NVP prophylaxis compromises subsequent HAART with NNRTI-based regimens.

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WHO Recommendations for the Use of ART for Maternal Treatment and Prevention of MTCT 

The new WHO recommendations aim to maximize access to high-quality services at the population level. TABLE 2, TABLE 3, TABLE 4, TABLE 5 give recommendations for various clinical situations; Table 6 provides dosing information for the regimens.

TABLE 2. Recommended antiretroviral regimens for prevention of MTCT in resource-limited countries in different scenarios⁴, ⁶

TABLE 3. Advantages and disadvantages of recommended and alternative antiretroviral prophylaxis regimens in resource-limited countries for pregnant women whose condition does not require therapy for their own health⁴

TABLE 4. Advantages and disadvantages of recommended and alternative antiretroviral prophylaxis regimens in resource-limited countries for pregnant women who have not received antepartum antiretroviral drugs⁴

TABLE 5. Advantages and disadvantages of recommended and alternative antiretroviral prophylaxis regimens in resource-limited countries for infants who are born to HIV-infected women who have not received antepartum or intrapartum antiretroviral drugs⁴

TABLE 6. Doses of antiretroviral prophylaxis drugs for prevention of MTCT of HIV⁴, ^6⁎

HIV-infected women who require ART for their own health 

A key principle of the new recommendations is that the condition of pregnant HIV-infected women should be evaluated for treatment eligibility and that women who are eligible for treatment should receive ART during pregnancy and should then continue on chronic treatment thereafter. A woman’s clinical stage and, where available, her CD4 cell count should be assessed to determine her eligibility for ART. CD4 cell counts are most important for asymptomatic women. To ensure that pregnant women who require ART are identified, efforts should be made to include CD4 cell count measurement in PMTCT programs or through efficient links between antenatal care and ART services. The choice of antiretroviral regimen in HIV-infected pregnant women must include consideration of fetal drug exposure, while assuring optimal treatment to preserve maternal health. The choice of ART in women with the potential to become pregnant must also include the consideration of the possibility of inadvertent fetal drug exposure during the primary period of fetal organ development.⁴⁸ The antiretroviral of most concern is efavirenz, because significant central nervous defects have been observed in infant monkeys with in utero efavirenz exposure at drug levels that are similar to those that are seen with human exposure at standard therapeutic doses and in 4 human infants with first-trimester exposure to efavirenz-containing regimens.⁴⁹, ⁵⁰, ⁵¹ Efavirenz should thus be avoided in women of childbearing potential who are not receiving adequate contraception and women in the first trimester of pregnancy. However, for women in whom effective contraception can be assured or women in the second or third trimester (in whom postpartum contraception can be assured), efavirenz is thought to be safe; this may be particularly important for women who are co-infected with tuberculosis, where efavirenz should be considered.

When to start HAART 

ART should be initiated in pregnant women with WHO clinical stage 4,⁵² WHO clinical stage 3 and CD4 count <350 cells/mm³, or WHO clinical stage 1 or 2 and CD4 count of <200 cells/mm³.⁶ The optimal time to initiate ART with a CD4 count between 200 and 350 cells/mm³ is unknown for asymptomatic women. Available data suggest that, if NNRTI-based ART is initiated <6 months after exposure to SD-NVP, viral suppression may be compromised⁴³, ⁴⁴; some women with CD4 counts between 200 and 350 cells/mm³ may require the initiation of therapy within the first year after delivery. Thus, some experts suggest that ART be considered for pregnant women with stage 1 or 2 and CD4 count of <350 cells/mm³, particularly for women with CD4 cell count nearing the threshold of 200 cells/mm³.

First-line regimen 

The recommended first-line regimen for pregnant women who are eligible for treatment is AZT + 3TC + NVP.⁶ These are the antiretroviral drugs with the greatest clinical experience with use in pregnant women and are known to reduce MTCT. However, toxicity, which includes hepatitis, is more common in women who begin receiving NVP-containing ART and who have a CD4 cell count of >250 cells/ mm³.⁵³, ⁵⁴, ⁵⁵, ⁵⁶ There are concerns about the initiation of NVP-containing ART in women with a CD4 cell count between 250 and 350 cells/mm³. This situation may arise because ART is recommended for pregnant women who have a CD4 cell count of <350 cells/ mm³ and WHO clinical stage 3 disease. In general, women have lower CD4 cell counts during pregnancy compared with after delivery, partly because of pregnancy-related hemodilution; the impact of this on the use of the CD4 350 cells/mm³ threshold in pregnant women, especially in women in clinical stage 1 or 2, is not known. Approaches to this issue include the initiation of a NVP-containing regimen with close monitoring in the first 12 weeks of therapy, the initiation of an efavirenz-containing regimen (if after 12 weeks of gestation and effective contraception can be assured after delivery), or the administration of a triple NRTI or a protease inhibitor (PI) based regimen.⁶ Each approach has advantages and disadvantages, and there are currently no data to favor 1 approach over the other.

HIV-infected pregnant women whose condition does not require ART or where ART is not available: antiretroviral prophylaxis for PMTCT 

HIV-infected women who are seen during pregnancy (TABLE 2, TABLE 3) 

The recommended regimen for antiretroviral prophylaxis of MTCT is AZT that is started at 28 weeks of gestation or as soon as feasible thereafter, intrapartum SD-NVP, and single-dose infant NVP combined with 1 week of AZT. In addition, intrapartum AZT/3TC followed by 7 days of maternal postpartum AZT/3TC is recommended to reduce the development of NVP resistance.⁴⁰ In situations in which infrastructure or availability of antiretrovirals is limited, at least the SD-NVP regimen should be given, ideally coupled with the intrapartum/postpartum AZT/3TC “tail”, if possible.

If the mother has received <4 weeks of AZT, the duration of infant AZT prophylaxis should be increased from 1-4 weeks. The recommendation for longer infant dosing when the mother has received only a short-course of antepartum AZT is based on the Thailand PHPT-1 study (Table 1), in which AZT that was started at 36 weeks of gestation and given to the infant for 4-6 weeks was superior to AZT that was started at 36 weeks of gestation and given to the infant for 3 days.¹⁰

Repeat dosing of maternal SD-NVP during labor in women who received a dose during “false labor” generally is not recommended because the risk of NVP resistance is higher after 2 NVP doses. Consideration can be given to the omission of the maternal intrapartum NVP dose if the mother has received >4 weeks of antepartum AZT, based on the Mashi data (Table 1).²⁵, ²⁶ Additionally, because transplacental NVP passage to the infant requires 1-2 hours, if delivery is imminent, maternal intrapartum NVP dosing may be omitted. When the maternal NVP dose is not received, the infant should receive SD-NVP immediately after birth and should receive 4 weeks rather than 1 week of AZT. No AZT/3TC tail is required if no maternal NVP is given.

HIV-infected women who are in labor and who have not received antiretroviral prophylaxis (TABLE 2, TABLE 4) 

The recommended regimen for women in labor who have not received antepartum antiretroviral prophylaxis (eg, women with a diagnosis of HIV late in pregnancy) is intrapartum SD-NVP combined with the intrapartum and 7-day postpartum AZT/3TC tail. The infant should receive SD-NVP combined with AZT for 4 weeks.

Alternative regimens include intrapartum AZT/3TC plus 1 week of infant and maternal AZT/3TC. This intrapartum/postpartum regimen had equivalent early efficacy to SD-NVP in the South African Nevirapine Trial (SAINT).¹⁴, ¹⁶ In settings with very limited infrastructure, the minimum intervention of SD-NVP to mother and/or infant should be administered.

Infants who are born to HIV-infected women who have not received antiretroviral drugs during pregnancy or labor (TABLE 2, TABLE 5) 

The recommended regimen for infants whose mothers have been unable to receive any antiretroviral prophylaxis is SD-NVP plus 4 weeks of AZT. Based on results from a randomized 4-group clinical trial in a nonbreastfeeding population in Thailand that investigated the efficacy of AZT prophylaxis that was given for varying durations to pregnant women and infants, the regimen that consists of SD-NVP and AZT for 4 weeks for the infant is likely to be more effective than SD-NVP and 1 week of AZT. ¹⁰ However, as noted earlier, the duration of recommended infant AZT is based on limited data, and 1 week is a potential alternative. Although infant-only SD-NVP was found to have equivalent efficacy to 6 weeks of AZT in a trial in South Africa,²⁴ the Nevirapine and Zidovudine (NVAZ) in Malawi demonstrated that, when the mother has not received any antiretroviral drugs, SD-NVP combined with 1 week of AZT is more efficacious than SD-NVP alone.¹⁹

HIV-infected women who are breastfeeding 

The WHO recommends exclusive breastfeeding for HIV-infected women for the first 6 months of life, unless replacement feeding is acceptable, feasible, affordable, sustainable, and safe for them and their infants before that time. When replacement feeding is acceptable, feasible, affordable, sustainable, and safe, avoidance of all breastfeeding by HIV-infected women is recommended.⁵⁷, ⁵⁸ For most resource-limited settings, breastfeeding remains the most feasible and sustainable option. However, breast milk is also an important route of HIV transmission, and there is great need to develop interventions that reduce or eliminate the risk of MTCT through breastfeeding. Trials are underway to assess the impact of antiretroviral drugs that are taken during breastfeeding on the risk of postnatal transmission of HIV and infant health. For breastfeeding women who meet the WHO criteria for the initiation of therapy for their own health, ART is recommended, because the benefit to the health of the woman outweighs potential risks to the infant. This symptomatic group of infected women, who have high viral loads and suppressed immune systems, is also likely the highest risk group to transmit HIV to their infant through breastfeeding.

The safety and efficacy of ART for the prevention of breast milk transmission in women who do not require ART for their own health remains a research question. The use of NVP in women with CD4 of >250 cells/mm³ carries a significant risk of hepatic toxicity; thus, alternative regimens are needed. There are very limited data about penetration of antiretrovirals into breast milk; if there is differential penetration, some drugs may have high levels, and others may have low or undetectable levels, which leads to the potential for the induction of drug-resistant HIV in milk and the potential for toxicity in the infant. Data from Botswana indicate that levels of NVP in breast milk of women who receive NVP-based ART were lower than in maternal plasma, although levels of 3TC and AZT in breast milk were 3-fold higher.⁵⁹ Data from Zimbabwe in women who were exposed to SD-NVP indicate that NVP resistance was found more frequently in breast milk than maternal plasma and that there were divergent resistance mutations found between breast milk and plasma.³² In 1 report, maternal ART was found to reduce cell-free (HIV RNA) levels in milk but did not affect cell-associated (HIV DNA) levels in milk.⁶⁰ Whether HIV RNA or DNA is more important in breast milk transmission is not known; some data suggest that cell-associated virus may be more important in the early months of breastfeeding.⁶¹ Thus, the risks and benefits of ART solely for the prevention of breast milk transmission must be elucidated more fully before this can be recommended. Several studies are currently ongoing to address this issue.⁶²

Several studies are also assessing the efficacy of antiretroviral prophylaxis to the breastfeeding infant to prevent MTCT. Observational studies have suggested this may be effective, but safety and efficacy must be validated in clinical trials before this can be recommended.⁶³, ⁶⁴

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Comment 

The WHO recommends a tiered approach for the delivery of antiretroviral drugs for treatment of HIV-infected pregnant women and for PMTCT of HIV in resource-limited settings that includes (1) ART for pregnant women who are eligible for treatment, (2) a combination PMTCT prophylaxis regimen for pregnant women who are not eligible for ART or where ART is not available, and (3) the maintenance of a minimum SD-NVP where more effective regimens are not yet available, although steps are taken to provide more effective regimens. To ensure that pregnant women who require ART are identified, efforts should be made to include CD4 cell count measurement in PMTCT programs or through active links between antenatal care and ART services. These interventions must also become part of routine maternal and child health and maternity activities at different levels of the healthcare system to address the HIV epidemic adequately.

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Acknowledgment 

We thank the WHO and the group of experts who participated in several WHO technical consultations that led to the development of these guidelines.

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