ANIMAL MODELS: WHAT CAN WE LEARN ABOUT PREVENTING RETROVIRUS TRANSMISSION DURING LACTATION?
Investigators at the California National Primate Research Center have been using simian immunodeficiency (SIV) infection of newborn and infant macaques as an animal model of pediatric HIV infection to study mechanisms of transmission and pathogenesis of disease progression and evaluate novel intervention strategies. This animal model allows researchers to test approaches that would be ethically or logistically difficult to test in human babies. Primate models are suitable because the physiology, immunology, and the mechanisms of viral transmission and disease pathogenesis are very similar to those of humans.
As the rate of SIV transmission from infected female macaques to their offspring is low and the timing is unpredictable, direct oral inoculation of the newborn or infant macaques was used to mimic intra- or postpartum transmission. These studies were performed with the highly virulent uncloned SIVmac251 isolate. The inoculum dose chosen induces persistent infection of 100% of untreated control animals and is undoubtedly higher than the amount of virus that would be encountered during a normal perinatal exposure. Accordingly, when an intervention strategy gives even partial protection in this highly virulent model, its efficacy in reducing intra- and postpartum infection may be even more pronounced for human newborns and infants.
A variety of chemo- and immunoprophylactic intervention strategies have been evaluated in this animal model. Initial antiretroviral drug studies demonstrated that a 6-week ZDV regimen or 3`-azido-3`-deoxythymidine, starting shortly before or at the time of virus inoculation, could protect some infant macaques against SIV infection, but the efficacy was low. 7,8 Subsequent studies demonstrated that tenofovir, a nucleotide reverse transcriptase inhibitor, is highly effective in preventing SIV infection. One or 2 subcutaneous doses of tenofovir were sufficient to protect newborn macaques against oral SIV infection, even when started shortly after virus inoculation 9,10 (Table 1). Tenofovir was still partially effective in protecting newborn macaques against oral infection with a virulent isolate with reduced in vitro susceptibility to this drug. 11 In addition to its high efficacy in this animal model, several other characteristics make tenofovir an attractive candidate to initiate human trials to reduce HIV transmission throughout the period of breast-feeding. Tenofovir has a long half-life, allowing a once-daily dosage regimen, does not induce resistance rapidly, and is relatively stable for storage. Tenofovir also has a promising safety profile, because prolonged daily treatment (>4 years) of infant macaques with a low-dose regimen that was pharmacokinetically still higher than the dose currently used in human patients was found to be safe (Van Rompay, K. et al, unpublished data).
INFANT PROPHYLAXIS DURING BREAST-FEEDING USING ANTIRETROVIRALS
Rationale and Advantages
In 1994 the first successful trial results (PACTG 076) using ZDV for perinatal HIV prevention were announced. 12 This regimen included both a maternal antiretroviral component to lower viral load prenatally as well as ZDV prophylaxis during labor and for 6 weeks postpartum to the neonate, and although thus the relative importance of either component could not be assessed in this trial, further observational studies have highlighted the infant postexposure prophylaxis component.
Since then, results from other studies in breast-feeding populations suggest that infant prophylaxis alone can substantially reduce the risk of transmission even without a reduction in prenatal maternal viral load. These include the HIVNET 12 study of single-dose NVP given to Ugandan mothers at labor onset and to the neonate, which effectively provided prophylaxis to the infant during the birth process and also through the first 1–2 weeks of breast-feeding due to the prolonged half-life of NVP. 13 At 6 weeks 13 and 12–18 months, 4 the risk of transmission was reduced by 41% for mother-infant pairs randomized to receive NVP compared with those mother-infant pairs who received intrapartum and 1 week of neonatal ZDV. The PETRA multicountry African trial demonstrated that ZDV/3TC given intra- and postpartum for 1 week to the mother and infant had a 42% efficacy at 6 weeks and an 18% efficacy at 18 months compared with placebo. 6 The SAINT trial in South Africa assessed 6-week transmission rates using either ZDV/3TC given at delivery and for 1 week postpartum compared with single-dose NVP given to the mother intrapartum and at 48 hours, and to the neonate. 14 Findings for the ZDV/3TC and NVP arms were similar at 6 weeks with transmission rates of 10 and 12%, respectively. These rates were also quite similar to the 6-week transmission rates seen in the original PETRA and HIVNET 012 studies. 6,13
Thus, findings from several trials in breast-feeding settings support the efficacy of ultrashort (intrapartum and 1 week postpartum) courses of infant antiretroviral prophylaxis using 3 different regimens (NVP, ZDV alone, ZDV/3TC) in reducing the risk of MTCT. However, these peripartum interventions do not address prevention of late breast-feeding transmission after the first weeks of life. 15–17
Infant Prophylaxis: Ongoing and Planned Studies
Given the animal and clinical trial data described here that support a role for infant prophylaxis, a number of trials are underway or being planned to assess the role of single or dual antiretroviral therapy given to the breast-fed, uninfected infant for varying lengths of time in reducing the risk of transmission during lactation (Table 2).
The timing of the postpartum interventions includes ultrashort regimens given in the first week of life to prevent transmission by colostrum or early breast milk; interventions covering the first 6–12 weeks of breast-feeding; and interventions that provide antiretroviral prophylaxis to the infant through the first 6 months of life accompanied by early weaning (see John-Stewart et al., p. 196 in this issue). In addition, planned vaccine and monoclonal passive immune approaches could theoretically protect the infant through extended breast-feeding into the second year of life (see Safrit et al. in this issue).
The rationale for trials that focus on the earliest period of lactation includes data from 2 studies suggesting a high transmission rate in the first weeks of life. The Nairobi infant feeding randomized trial assessed differences in transmission rates between breast- and formula-fed infants between day 1 and week 6 and found a difference of 6.3% among infants who had been negative at birth. 18 Likewise, the SAINT study found that among infants who were HIV negative at birth, there was a 5.6% difference in acquisition of HIV by 8 weeks among breast- and formula-fed infants. 14
Short-Term Infant Antiretroviral Prophylaxis (1 Week)
Whether 1 week with mono or dual antiretroviral prophylaxis to neonates can protect against peripartum and very early HIV transmission through breast-feeding is being investigated in separate trials in Malawi and South and West Africa.
Preliminary results from a randomized controlled trial in Malawi showed that among infants whose mothers had not received intrapartum antiretrovirals, the transmission rate was 22% at 6 weeks for infants who received single-dose NVP given soon after birth compared with 14% for those who received single-dose NVP plus ZDV given twice a day for 1 week. 19 These preliminary findings suggest that dual antiretroviral prophylaxis to the neonate may be more effective than use of a single drug.
Preliminary results from a randomized trial in South Africa, where only 20% of the mothers breast-fed, showed that overall, infants had a similar reduced risk of peripartum HIV transmission at 6 weeks when they were randomly assigned to receive either a single dose of NVP soon after birth (7.3%) or 6 weeks of ZDV from birth (10.7%). 20 Of note, in the minority of infants who were breast-fed, prophylaxis with single-dose NVP was associated with a lower risk of peripartum transmission (9.5%) than with 6 weeks of ZDV (28.2%).
In the ANRS1202 DITRAME Plus trial 21 in Côte d'Ivoire, the efficacy of maternal prenatal ZDV (now ZDV/3TC) in the last 4 weeks of pregnancy plus 1 week of infant ZDV together with single-dose NVP given to the mother intrapartum and to the newborn (now with 1 week of ZDV) is being assessed. Transmission rates were compared with historical data from the short-course ZDV trial results. 5 Early findings from this study indicate a 6.2% transmission rate at 6 weeks postpartum for the dual ZDV and single-dose NVP regimen compared with a historical transmission rate of 14.7% for the short-course antenatal/intrapartum ZDV regimen in the pooled West African analyses. This decrease in transmission with the addition of single-dose NVP to the short-course prenatal ZDV regimen may be related to dual-drug prophylaxis of the neonate during labor, delivery, and the first week of life.
Intermediate Duration of Infant Antiretroviral Prophylaxis (6 Weeks)
Three different but affiliated randomized clinical trials are planned or underway in Ethiopia, Uganda, and India. All mother-infant pairs will receive NVP as per the HIVNET 012 regimen (1 dose to the mother at the onset of labor and 1 dose to the baby within 72 hours of birth). All mothers will be breast-feeding and will be advised to stop when the child is 6 months old.
In India, a 2-arm study comparing single-dose NVP vs. 6 weeks of infant NVP began enrollment in late 2002. All mothers receive ZDV twice a day from 36 weeks of pregnancy, and all infants receive multivitamin supplementation during the first 6 weeks postpartum. Infants are randomly assigned to receive either the HIVNET 012 single-dose NVP regimen alone or the HIVNET 012 regimen followed by a daily dose of NVP from day 8 until age 6 weeks, as an open-label study. The study assesses the safety of the extended postpartum NVP regimen and its efficacy compared with the single-dose NVP regimen for the prevention of infant HIV acquisition through breast-feeding.
In Ethiopia, the Nigat project also started in 2002 in Addis Ababba. All mothers receive the single-dose NVP at onset of labor. Their infants are randomly assigned to receive either multivitamin alone or multivitamin and NVP daily from day 8 until age 6 weeks, in a blinded fashion. This trial will examine the safety of the postpartum infant NVP regimen and its efficacy for the prevention of infant acquisition of HIV through breast-feeding, as well as compliance issues. A cohort of HIV-infected nonbreast-feeding mothers and one of HIV-negative mothers will also be studied.
In Uganda, the HIVIGLOB/NVP study, anticipated to start in 2003, is a 3-arm randomized phase 2 trial to compare HIV infection rates in HIV-exposed breastfed infants receiving 1 of 3 interventions. In the control arm 1, mother-infant pairs will receive NVP as per HIVNET 012; in arm 2, infants will additionally receive NVP from day 8 until age 6 weeks; and in arm 3, pregnant women will receive an infusion of HIV-specific immunoglobulins at 37 or 38 weeks of pregnancy and their infants an infusion of the same within the first 18 hours of life, in addition to single-dose NVP.
Prolonged Duration of Infant Antiretroviral Prophylaxis (6 Months)
The SIMBA 2-armed trial assesses the effectiveness and tolerance of postnatal prophylactic treatment with either 3TC or NVP in infants during the first 6 months of breast-feeding to prevent HIV-1 transmission. All mothers received a combination of ZDV and didanosine (ddI) twice a day starting at 36 weeks of pregnancy until 1 week postpartum, increased to every 3 hours during delivery. This study, conducted in Uganda and Rwanda, recently completed enrollment. HIV-negative infants were randomly allocated to receive NVP or 3TC twice a day during the period of breast-feeding, with a recommendation of cessation of breast-feeding after a maximum of 6 months. The first interim look at study results is expected mid-2003.
The MITRA study in Tanzania is an open-label 1-arm study in which HIV-infected pregnant women receive ZDV and 3TC in the last 4 weeks of pregnancy and during labor and delivery and their infants receive 6 months of 3TC prophylaxis with weaning at 6 months. Results from this study are expected in 2004.
The Mashi study in Botswana will compare HIV transmission rates between infants formula-vs. breast-fed, with ZDV provided to uninfected infants as prophylaxis. All mothers receive ZDV from 34 weeks of pregnancy and intrapartum. The study also looks at the impact of adding NVP as per the HIVNET 012 regimen. It is a randomized trial using a factorial design for treatment (mother and infant receiving NVP or not) and infant feeding mode allocation. All breast-feeding mothers will be advised to stop breast-feeding rapidly (over a 2-week period) at 4–6 months. All mothers with CD4 cell count <200/mm3 will receive highly active antiretroviral therapy (HAART).
The HPTN 046 study will determine the efficacy and safety of an extended regimen of NVP in infants born to HIV-positive women to prevent vertical HIV transmission during breast-feeding. It will be conducted in South Africa, Tanzania, Uganda, and Zimbabwe. All mother-infant pairs will receive NVP as per HIVNET 012. Breast-feeding children will be randomly allocated to receive the standard of care or NVP daily till 6 months of age, with incremental dose increase from 6 mg per day during the first 2 weeks of life to 28 mg per day from 5–6 months of age. These dosages are based on the results of a phase 1/II study that preceded the efficacy trial, in which safety and plasma concentrations of NVP were compared in breast-fed infants receiving daily, twice a week, or weekly doses as HIV prophylaxis. All mothers will be advised to abruptly wean at 6 months. 22
USE OF MATERNAL HIGHLY ACTIVE ANTIRETROVIRAL THERAPY TO PREVENT MOTHER-TO-CHILD-TRANSMISSION IN BREAST-FEEDING SETTINGS
Rationale and Advantages
Maternal viral load is one of the most important risk factors for perinatal transmission in both breast-feeding and nonbreast-feeding populations. Presence of detectable virus in breast milk was found associated with infant infection risk in studies in Malawi 23 and in South Africa. 24 Studies in the United States have documented the lowest rates of transmission among nonbreast-feeding women receiving highly potent combination therapy 1,2 with rates of ≤2%; and in a meta-analyses by Ioannidis et al., 25 the rate of MTCT was <1% for women whose viral load was <1000 copies/mL near the time of delivery. Based on these findings, it is likely that giving HAART during late pregnancy and during lactation to HIV-infected women in resource-limited settings could substantially reduce the risk of transmission by lowering viral load. Use of maternal HAART could also potentially improve maternal immune and clinical status, which would reduce MTCT and improve the woman's own health.
Providing HAART to HIV-infected pregnant women and breast-feeding mothers, and continuing it if the woman meets criteria for ongoing treatment, would provide the link between prevention and care. This would likely improve uptake of MTCT prevention interventions, which are so far directed only toward the prevention of HIV infection to infants, with very little benefit to their mothers. This is especially true now that HAART is becoming increasingly available in resource-limited countries through various initiatives. Use of HAART as opposed to single or dual therapy given to pregnant women would also theoretically prevent the development of resistance seen in 19% of women given single-dose NVP (see John-Stewart et al. in this issue).
Current Maternal HAART Trials Among HIV-Infected Women in Resource-Limited Settings
Three perinatal prevention trials are planned in African settings to evaluate the use of maternal HAART to reduce the risk of HIV transmission during the late prenatal period and during breast-feeding; all 3 use a combination of 2 nucleoside reverse transcriptase inhibitors (NRTIs) (ZDV+3TC) and 1 nonnucleoside reverse transcriptase inhibitor (NNRTI) (NVP). This regimen is the first-line HAART regimen recommended by the World Health Organization (WHO) when used as therapy for pregnant women in resource-limited settings. 26 It has been selected for reasons of potency, safety for the mother and the baby, practicality (low pill burden, no need for refrigeration), and cost. The regimen has also been used for several years in the United States and Europe with acceptable safety.
The Kisumu breast-feeding study, which will be conducted in western Kenya, is a phase 2 open-label 1-arm trial. It aims at demonstrating that the use of HAART to maximally suppress maternal viral load in the late antenatal period and during the first 6 months of lactation is safe, well tolerated, effective, and can be implemented in resource-poor settings to reduce the risk of HIV transmission to infants. All pregnant women will receive HAART from 34–36 weeks of pregnancy, during delivery, and for 6 months while breast-feeding. Neonates will also receive a single dose of NVP soon after birth. Efficacy comparisons will be made using historical data from the HIVNET 012 study in Uganda, a vertical malaria HIV study recently completed in Kisumu, and a proposed cohort to evaluate the MTCT prevention program at the Provincial Hospital in Kisumu, which give NVP according to the HIVNET 012 regimen. Women who meet WHO criteria for treatment will be continued on HAART.
The University of North Carolina and Centers for Disease Control will be conducting a randomized trial in Lilongwe, Malawi. Its main objectives are to decrease MTCT among breast-feeding HIV-infected mothers, decrease maternal morbidity and mortality during breast-feeding, and enhance nutritional status of HIV-infected mothers and infants through feasible nutrition counseling and maternal nutritional supplementation. It will be a factorial design in which all pregnant women with CD4 counts > 200 cells/mm3 will be randomly assigned to receive or not receive supplementation with a nutritional bar twice daily during pregnancy and breast-feeding. A second level of randomization will be for antiretrovirals. All women will receive single-dose NVP intrapartum and 1 week of ZDV/3TC postpartum and their newborns will receive single-dose NVP and 1 week of ZDV/3TC postpartum. At 1 week, mother-infant pairs will be randomly assigned to 1 of 3 open-label arms: no further antiretrovirals to either mother or infant; maternal HAART with ZDV/3TC/NVP until 28 weeks postpartum while breast-feeding; or infant NVP given daily for 28 weeks while breast-feeding, with early weaning. Women with CD4 counts < 200 cells/mm3 will not be part of the randomized trial but will be referred for HAART as part of programmatic efforts in Lilongwe. Infants will be weaned from 24–28 weeks and provided with ready-to-eat food.
The multicountry Kesho Bora study coordinated by the WHO will assess the impact, tolerability, and acceptability of a strategy providing HAART to HIV-infected pregnant women (breast-feeding and nonbreast-feeding) according to CD4+ cell level. All women with CD4 cells < 200/mm3 will receive prolonged HAART. All women with CD4 cells >500/mm3 will receive a short-course regimen: a combination of ZDV given to the mother from 34–36 weeks of pregnancy and during delivery, and one dose of NVP during labor as per HIVNET 012. Women with intermediate CD4 counts between 200–500/mm3 will be randomly assigned to receive either the standard short-course ZDV plus single-dose NVP at labor; or HAART from 34–36 weeks of pregnancy either through delivery if they are formula feeding or until 6 months postpartum if they breast-feed with early weaning. Infants in all groups will receive a single dose of NVP during the first 72 hours of life. It is expected that more than half of the women in the selected sites will choose to breast feed.
These studies also include nested laboratory studies that will assess immune and viral characteristics associated with infectivity of breast milk, pharmacokinetics of drugs, and patterns of viral load reduction and drug resistance emergence.
Potential Side Effects and Toxicity Considerations Related to Use of Maternal or Infant Prophylaxis Regimens
Maternal Drug Toxicity
ZDV and 3TC are NRTIs that have been associated with hematologic and hepatic toxicity. These toxicities are usually moderate in severity and reversible after treatment interruption. Other rarer toxic effects linked to NRTIs include lactic acidosis, pancreatitis, and mitochondrial dysfunction and the HELLP (hepatic, elevated liver and low platelet) syndrome among pregnant women. 27 No increase in the frequency of congenital malformations or malignancies has been reported during follow-up of children exposed in utero to ZDV in the PACTG 076 trial and in observational cohorts. 28–30 The most frequent side effects of the drugs are nausea, headache, myalgia, loose stools, and insomnia. Their incidence usually decreases with time.
The most common toxicities seen with NVP, an NNRTI, are rash and hepatotoxicity. Rarely severe, life-threatening, and in some cases fatal hepatotoxicity has been reported in HIV-infected patients receiving NVP in combination with other drugs for treatment of HIV disease 31 and in a small number of individuals receiving NVP as part of a combination regimen for postexposure prophylaxis of nosocomial or sexual HIV exposure. 32 Grade I-II rash is seen in about 15–20% of patients and its frequency is reduced by use of a 2-week lead-in with a reduced dose of NVP. Severe, life-threatening idiosyncratic hypersensitivity skin reactions, including Stevens-Johnson Syndrome (SJS), have been rarely reported in HIV-positive individuals receiving NVP for treatment, usually during the first 12 weeks of therapy, and the incidence of SJS is estimated at about 0.3% among adult populations in the United States. 31
Infant Drug Toxicity
Anticipated toxicities among infants are similar to those among adults. All 3 drugs (ZDV, 3TC, and NVP) for the maternal HAART studies are transferred into breast milk, 13,33,34 but the daily dose of these antiretrovirals that an infant would ingest through breast-feeding is estimated to be between 10–20 times lower than the usual therapeutic dose, and therefore the risk of most toxicities in infants is likely to be low. However, development of resistance to antiretrovirals is possible since infants will be receiving subtherapeutic levels of drugs for relatively long periods, at least in some of the planned regimens (see John-Stewart et al., p. 196 in this issue).
The most common toxicity for ZDV is anemia. In the PACTG 076 study, 19% of infants on ZDV had anemia and 2% had severe anemia, while anemia was rare in those receiving placebo. 12 With the short-course ZDV regimens, less infant anemia has been reported in studies in Thailand, 35 Malawi, 19 South Africa, 14 and West Africa. 21 There are no data currently available on the safety of prolonged ZDV prophylaxis given to uninfected infants for up to 6 months. Of note, grade III or above neutropenia was reported in about 25% of infants on both the placebo and ZDV arms of the PACTG 076 trial, 36 which would suggest lower normal values for neutrophil counts among African American populations. This may have relevance to African populations.
The safety of 3TC in infants has been evaluated when used in combination with ZDV. A study in France looked into the efficacy and safety of adding 3TC to ZDV given to mothers from 32 weeks' pregnancy and to the child for 6 weeks after birth. 37 Among the 437 infants evaluated, the most frequent serious adverse events in children were neutropenia and anemia. In African breast-feeding populations, 2 trials (SAINT 14 and PETRA 6) included an assessment of the safety of ZDV/3TC given to neonates. In PETRA, 6 infants who received ZDV/3TC had similar rates of laboratory abnormality grade 3 or 4 (5%), congenital abnormality (7%), or neurologic events (2%) than infants in the placebo group. The SAINT trial (141) in South Africa compared ZDV/3TC given intrapartum and 1 week postpartum to mothers and infants to single-dose NVP given to mothers at delivery and to their neonates and found both regimens to be safe and well tolerated. Long-term safety of prolonged 3TC for 6 months in uninfected infants is currently being assessed in the MITRA and SIMBA studies.
The safety and pharmacokinetics of long-term use of NVP in infants from birth has only been evaluated in the phase 1/II HIVNET 023 study assessing those issues among breast-ed infants receiving NVP either daily, twice a week, or weekly from birth to 24 weeks as HIV prophylaxis. 22 Preliminary results showed ≥ grade 3 neutropenia in about one third of infants. Given that the SJS reaction to NVP is not dose dependent, infants are at risk for such toxicity even with low levels of drug exposure through breast milk. No cases of SJS have been reported with the single-dose NVP regimen based on safety data from >1300 mother-infant pairs across 3 perinatal clinical trials. 28
Late Outcomes Among Infants Exposed to Perinatal Antiretroviral Regimens
There were no differences in growth, immunologic, neurologic, or neurodevelopmental characteristics or in the development of malignancy between ZDV-exposed and not-exposed infants in the PACTG 076 trial. 29 Rare mitochondrial dysfunction, including 2 fatal cases possibly associated with the in utero/postnatal exposure to ZDV/3TC, has been reported in a French cohort. 38 However, this finding has not been confirmed in a retrospective analysis of data from the major US perinatal cohorts comprising >16,000 uninfected children 39 or in a European cohort study. 30
Due to potential for increased hematologic or hepatic toxicity in resource-limited settings with a background of infectious diseases such as malaria and hepatitis B, the planned trials will include a close clinical and laboratory monitoring of women and children.
Trials utilizing maternal HAART plan to interrupt therapy after 6 months of breast-feeding among mothers who do not require this treatment of their own health according to WHO criteria. In adult studies, a peak of plasma viral load above the baseline level has been reported immediately following treatment interruption. In breast-feeding mothers it might be associated with a peak of viral load in breast milk as well as plasma, potentially leading to a higher short-term risk of HIV transmission both to infants through breast-feeding and to women's sexual partners. It would therefore be important to stop all breast-feeding before HAART cessation and to ensure that condoms were used consistently among discordant couples. The long-term impact of stopping treatment of women receiving HAART for perinatal HIV prophylaxis will need to be carefully studied both in resource-limited and resource-rich settings. The longer half-life of NVP would warrant continuation of the nucleosides for a few days after stopping NVP.
The present overview indicates that the planned studies address many of the important research questions concerning prevention of postnatal HIV transmission during lactation by means of antiretroviral drugs. Several clinical trials are now in development or being conducted in Africa or other resource-limited settings. These trials use a variety of different antiretroviral regimens either given singly or as dual prophylaxis to neonates and young infants, as well as HAART regimens given to HIV-infected mothers during the late prenatal period and the first 6 months of breast-feeding. Laboratory studies nested within several of these trials will provide a better understanding of the pathogenesis of postnatal HIV transmission and its potential prevention using antiretroviral drugs. Preliminary results from a number of these trials should become available over the next several years. They will provide useful information to guide programs on reducing breast milk transmission of HIV in the same way the results from the peripartum short-course perinatal trials guided the initiation and development of current MTCT prevention efforts.
Dr. van der Horst is supported by NIH grants AI-98-013 Adutl-ACTG-ACTU, NICHD/NIAID p30-HD37260, AI-01-018 CIPRA, and CDC grant Special Interest Project 13-01 U48/CCu409660-9.
1. Dorenbaum A, Cunningham CK, Gellber RD, et al. Two-dose intrapartum/newborn nevirapine and standard antiretroviral therapy to reduce perinatal HIV transmission. JAMA. 2002; 288:189–198.
2. Cooper ER, Charurat M, Mofenson L, et al. Combination antiretroviral strategies for the treatment of pregnant HIV-1 infected women and prevention of perinatal HIV-1 transmission. J Acquir Immune Defic Syndr. 2002; 29:484–494.
3. De Cock KM, Fowler MG, Mercier E, et al. Prevention of mother-to-child HIV transmission in resource-poor countries: translating research into policy and practice. JAMA. 2000; 283:1175–1182.
4. Jackson JB, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18 month follow-up to the HIVNET012 randomized trial. Lancet. 2003; 362:59–68.
5. Leroy V, Karon JM, Alioum A, et al. Twenty-four month efficacy of a maternal short-course zidovudine regimen to prevent mother-to-child transmission of HIV-1 in West Africa. AIDS. 2002; 16:631–641.
6. The Petra Study Team. Efficacy of three short-course regimens of zidovudine and lamivudine in preventing early and late transmission of HIV-1 from mother to child in Tanzania, South Africa, and Uganda (Petra study): a randomised, double blind, placebo-controlled study. Lancet. 2002; 359:1178–1186.
7. Van Rompay KKA, Otsyula MG, Martas ML, et al. Immediate zidovudine treatment protects simian immunodeficiency virus-infected newborn macaques against rapid onset of AIDS. Antimicrob Agents Chemother. 1995; 39:125–131.
8. Van Rompay KKA, Marthas ML, Ramos RA, et al. Simian immunodeficiency virus (SIV) infection of infant rhesus macaques as a model to test antiretroviral drug prophylaxis and therapy: oral 3`-azido-3`-deoxythymidine prevents SIV infection. Antimicrob Agents Chemother. 1992; 36:2381–2386.
9. Van Rompay KKA, Berardi CJ, Aguirre NL, et al. Two doses of PMPA protect newborn macaques against oral simian immunodeficiency virus infection. AIDS. 1998; 12:F79–F83.
10. Van Rompay KKA, McChesney NL, Aguirre KA, et al. Two low doses of tenofovir protect newborn macaques against oral simian immunodeficiency virus infection. J Infect Dis. 2001; 184:429–438.
11. Van Rompay KKA, Miller DM, Marthas ML, et al. Prophylactic and therapeutic benefits of short-term 9-[2-(phosphonomethoxy)propyl]adenine (PMPA) administration to newborn macaques following oral inoculation with simian immunodeficiency virus with reduced susceptibility to PMPA. J Virol. 2000; 74:1767–1774.
12. Connor EM, Sperling RS, Gelber RS, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1994; 331:1173–1180.
13. Guay L, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet. 1999; 354:795–802.
14. Moodley D, Moodley J, Coovadia H, et al. A multicentre randomized controlled trial of nevirapine versus a combination of zidovudine and lamivudine to reduce intrapartum and early postpartum mother-to-child transmission of human immunodeficiency virus type 1. J Infect Dis. 2003; 187:725–735.
15. Miotti PG, Taha TE, Kumwenda NI, et al. HIV transmission from breastfeeding: a study in Malawi. JAMA. 1999; 282:744–749.
16. Read JS, Newell M-L, Leroy V, et al. Late postnatal transmission of HIV in breastfed children: an individual patient data meta-analyses (The Breastfeeding and HIV International Transmission Study). Paper presented at: Tenth Conference on Retroviruses and Opportunistic Infections; February 10–14, 2003; Boston. Abstract 97.
17. Leroy V, Newell ML, Dabis F, et al. International multicentre pooled analyses of late postnatal mother-to-child transmission of HIV-1 infection. Lancet. 1998; 352:597–600.
18. Nduati R, John GC, Mbori-Ngacha D, et al. Effect of breast-feeding and formula feeding on transmission of HIV-1: a randomized clinical trial. JAMA. 2000; 283:1167–1174.
19. Taha TE, Kumwenda N, Gibbons A, et al. Short postexposure prophylaxis in newborn infants to reduce mother-to-child transmission of HIV-1: NVAZ randomized clinical trial. Lancet. 2003; 362:1171–1177.
20. Gray G, Urban M, Violoar A, et al. Preliminary analysis of a randomised controlled study to assess the role of post-exposure prophylaxis in reducing mother to child transmission of HIV-1. Paper presented at: XIV International AIDS Conference; July 7–12, 2002; Barcelona. LB0R13
21. Dabis F, Ekouevi DK, Bequet K, et al. A short course of zidovudine + peripartum nevirapine is highly efficacious in preventing mother-to-child transmission of HIV-1: the ANRS 1201 DITRAME-plus Study, Abidjan, Côte d'Ivoire. Paper presented at: 10th
Conference on Retroviruses and Opportunistic Infections; February 10–14, 2003; Boston. Abstract 854.
22. Shetty A, Coovadia HM, Maldonado Y, et al. HIVNET 023: a phase I/II study of the safety and plasma concentrations of nevirapine given daily, twice a week or weekly as HIV prophylaxis in breastfeeding infants from birth to 24 weeks in Durban, South Africa and Harare, Zimbabwe. Paper presented at: 3rd Conference on the Global Strategies for the Prevention of HIV Transmission from Mothers to Infants; September 9–13, 2001; Kampala, Uganda. Abstract 123.
23. Semba RD, Kumwenda N, Hoover DR, et al. Human immunodeficiency virus load in breast milk, mastitis, and mother-to-child transmission of human immunodeficiency virus type 1. J Infect Dis. 1999; 180:93–98.
24. Pillay K, Coutsoudis A, York D, et al. Cell-free virus in breast milk of HIV-1 seropositive women. J Acquir Immune Defic Syndr. 2000; 24:330–336.
25. Ioannidis JP, Abrams EJ, Amman A, et al. Perinatal transmission of human immunodeficiency virus type 1 by pregnant women with RNA virus loads <1000 copies/ml. J Infect Dis. 2001; 183:539–545.
26. WHO (2002). Scaling up antiretroviral therapy in resource-limited settings: guidelines for a public health approach. Available at: http://www.who.int/hiv/pub/sti/pub6/en/
accessed March 3, 2003.
27. Mofenson LM, Munderi P. Safety of antiretroviral prophylaxis of perinatal transmission for HIV for HIV-infected pregnant women and their infants. J Acquir Immune Defic Syndr. 2002; 30:200–215.
28. Culnane M, Fowler MG, Lee SS, et al. Lack of long-term effects of in utero exposure to zidovudine among uninfected children born to HIV-infected women. JAMA. 1999; 281:151–157.
29. Hanson IC, Antonelli TA, Sperling RS, et al. Lack of tumors in infants with perinatal HIV-1 exposure and fetal/neonatal exposure to zidovudine. J Acquir Immune Defic Syndr Hum Retrovirol. 1999; 20:463–467.
30. European Collaborative Study. Exposure to antiretroviral therapy in utero or early life: the health of uninfected children born to HIV-infected women. J Acquir Immune Defic Syndr. 2003; 32:380–387.
31. Public Health Service Task Force. Recommendations for the use of antiretroviral drugs in [regnant HIV-1 infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States. MMWR Recomm Rep. 2002; 51(RR-18):1–38
32. Centers for Disease Control and Prevention. Serious adverse events attributed to nevirapine regimens for postexposure prophylaxis after HIV exposures worldwide, 1997–2000. MMWR Morb Mortal Wkly Rep. 2001; 49:1153–1156.
33. Moodley J, Moodley D, Pillay K, et al. Pharmacokinetics and antiretroviral activity of lamivudine alone or when coadministered with zidovudine in human immunodeficiency virus type 1-infected pregnant women and their offspring. J Infect Dis. 1998; 178:1327–1333.
34. Musoke P, Guay LA, Bagenda D, et al. A phase I/II study of the safety and pharmacokinetics of nevirapine in HIV-1-infected pregnant Ugandan women and their neonates (HIVNET 006). AIDS. 1999; 13:479–486.
35. Shaffer N, Chuachoowong R, Mock PA, et al. Short-course zidovudine for perinatal HIV-1 transmission in Bangkok, Thailand: a randomised controlled trial. Lancet. 1999; 353:773–780.
36. Sperling RS, Shapiro DE, McSherry GD, et al. Safety of the maternal-infant zidovudine regimen used in the Pediatric AIDS Clinic Trials Group 076 study. AIDS. 1998; 12:1805–1813.
37. Mandelbrot L, Landreau-Mascaro A, Rekacewica C, et al. Lamivudine-zidovudine combination for prevention of maternal-infant transmission of HIV-1. JAMA. 2001; 285:2083–2093.
38. Blanche S, Tardieu M, Rustin P, et al. Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet. 1999; 354:1084–1089.
39. Perinatal Safety Review Working Group. Nucleoside exposure in the offspring of HIV-infected women receiving antiretroviral drugs: absence of clear evidence for mitochondrial disease in children who died before 5 years of age in 5 U.S. cohorts. J Acquir Immune Defic Syndr Hum Retrovirol. 2000; 25:261–268.