a Division of Infectious Diseases, Bronx-Lebanon Hospital Center, Bronx, New York b Division of Infectious Diseases, Beth Israel Medical Center, New York c Albert Einstein College of Medicine, Bronx, New York, NY, USA
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Abstract |
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Introduction |
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The incidence of HIV infection among women in resource-rich nations has increased greatly in recent years.3 The introduction of potent, highly effective antiretroviral therapy (ART) in the mid-1990s has had a profound effect on AIDS mortality, leading to an increase in the prevalence of people living with HIV.4 The combination of these two trends is likely to result in greater numbers of HIV-infected women choosing to become pregnant.
The Pediatric AIDS Clinical Trials Group Protocol 076 (PACTG 076) demonstrated the effectiveness of ART for prevention of perinatal transmission of HIV.5 This trial was the proof of principle upon which many subsequent controlled trials and treatment guidelines have been based. The study, conducted in the USA and published in 1994, used zidovudine monotherapy in three parts: (i) prenatally beginning at/after 14 weeks' gestation; (ii) as an iv infusion during labour; and (iii) as chemoprophylaxis for 6 weeks in exposed newborns. Zidovudine use was associated with a significant decrease in perinatal HIV transmission from 25.5% in the placebo group to 8.3%.
The results of PACTG 076 were exciting and, where possible, zidovudine prophylaxis in HIV-infected pregnant women has been widely adopted. However, a number of important issues have evolved with regard to the interpretation and extrapolation of these findings for broader use. First, what aspect of zidovudine activity is responsible for its benefit, and does its reduction of HIV viral load account fully for decreased transmission? If so, more potent combinations, with less potential for viral resistance to emerge, might be expected to do even better. Also, is zidovudine unique among antiretrovirals as a prophylactic agent at reducing perinatal transfer of HIV? If so, does it need to be included in the therapeutic regimen of all pregnant HIV-infected women even if the mother harbours a zidovudine-resistant strain? Secondly, which aspect of prophylaxis (i.e. ante-partum, intra-partum or post-partum) is most critical, and are all components necessary? The answer to this question is important since the estimated cost of the full PACTG 076 course of therapy (approximately US$800) and its complexity restrict the use of this regimen in nations with limited resources.6 If prophylaxis could be given when its effect would be most profound, more limited intervention might be possible, and hence more individuals could be treated for a given cost. Knowledge of the optimal timing of ART would be helpful also in developed countries since many women present late in pregnancy or at the time of labour. Another issue not addressed by PACTG 076 was the role of breastfeeding on perinatal transmission of HIV and the safety and efficacy of alternatives, such as formula feeds or more extensive post-partum ART. None of the women enrolled in PACTG 076 practised breastfeeding. Lastly, non-ART interventions may affect HIV transmission. Elective Caesarean section, antiseptic washes and vitamin supplementation have been suggested as potentially useful adjuncts to ART.
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Risk factors for perinatal HIV infection |
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In industrialized nations, perinatal HIV transmission rates without ART range between 14 and 26%, whereas in developing nations the rates range from 21 to 43%.5,13 Breastfeeding probably accounts for this disparity. Since the risk is not uniform it is important to recognize the factors that affect perinatal acquisition of HIV (Table I).
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Levels of HIV in maternal genital tract secretions may affect vertical transmission.21 Elective Caesarean section has been studied as a way of preventing the newborn coming into contact with these infected fluids. Obstetric factors such as rupture of membranes for >4 h, placental abruption, amniocentesis, chorionic villus sampling, use of fetal scalp electrodes, episiotomy, the presence of vaginal lacerations during labour or preterm delivery associated with prolonged membrane rupture, may increase exposure of the fetus to maternal blood and body fluids and have been identified as important risk factors for perinatal HIV transmission.2224 The presence of chorioamnionitis or genital ulcers can further increase peri-partum risk of transmission.15,2527 Increased cervicovaginal HIV DNA levels are related to low CD4+ cell counts, severe vitamin A deficiency and vaginal discharge.21 ART has been shown to decrease HIV RNA levels in cervicovaginal lavage and reduce vertical transmission.28
Breastfeeding is responsible for most post-partum HIV transmission.29 It has been estimated that the risk of HIV transmission from breastfeeding is 14% from mothers with established HIV infection and 29% from mothers who acquire HIV after birth.30 Breast milk HIV viral loads correlate with plasma viral loads and are at their peak during and just after seroconversion. Most HIV infection of the infant from breastfeeding occurs during the first 6 weeks of life, with a lower risk thereafter.31 Transmission of HIV by breastfeeding is increased in the setting of low maternal CD4+ cell counts, mastitis and prolonged exposure.3234 Antibodies to HIV in breast milk are not protective.35
T-helper cell responses to HIV-specific antigens in newborns may also play an important role in determining whether infants exposed to HIV in all stages of pregnancy and via breastfeeding will become infected. A recent study of a breastfeeding population in Africa found no HIV transmission to infants in whom there was early development of T-helper cell responses to HIV envelope peptides, whereas there was 17% transmission in those without such a response.36 The time of development and protective role of these immune responses need further study.
Decreased CD4+ cell counts are a measure of worsening immune deficiency and have been associated with enhanced perinatal HIV transmission.15 However, a low CD4+ cell count may result from a high viral load and, therefore, may not be an independent risk factor for vertical acquisition of HIV.15 Vitamin A deficiency and malnutrition can cause immune deficiency and disruption of mucosal integrity and are associated with increased vertical HIV transmission.37 However, vitamin A supplementation during pregnancy has not provided significant benefit in prevention of perinatal HIV infection.38,39
Maternal use of illicit drugs such as cocaine and heroin has been associated with a risk up to three-fold higher of delivering an HIV-infected baby.40 Cigarette smoking during pregnancy may also increase the risk of transmission.41 The potential risk from drug use appears to be most pronounced when the proportion of CD4+ cells is high (>29%).40
HIV must interact with both CD4+ cells and a chemokine receptor to infect a T-lymphocyte.42 Recent studies have demonstrated that mutations in these co-receptors or the genes that regulate their expression may render a CD4+ cell more or less vulnerable to infection by HIV.4345 Philpott et al.46 studied HIV transmission rates among 552 motherinfant pairs and found no infected babies among those homozygous for a 32 base pair deletion in a chemokine receptor gene (CCR5). Further understanding of the effect of HIV co-receptors on vertical transmission rates is needed.
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Antiretroviral therapy to prevent perinatal HIV transmission |
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The major prospective clinical trials of ART to prevent perinatal HIV transmission are summarized in Table II. As mentioned above, PACTG 0765 showed a 68% reduction of vertical HIV transmission with the use of zidovudine in three stages: prolonged antenatal, intra-partum and post-partum dosing. PACTG 18547 was designed to determine whether HIV-specific immunoglobulin administered prenatally with a single post-partum dose was more effective than zidovudine alone. The protective effect of maternal or passively administered antibody to prevent vertical HIV transmission has been controversial.4850 The study demonstrated no benefit from the addition of HIV-specific immunoglobulin. However, the low transmission rate (5%) confirmed the efficacy of zidovudine given as in PACTG 076. This benefit was also observed in women with lower CD4+ cell counts (median 306 cells/mm3 in PACTG 185 and 550 cells/mm3 in PACTG 076) and in the 24% of mothers in the study who had zidovudine exposure before pregnancy.
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The PETRA trial55 compared HIV vertical transmission rates in pregnant women who received either a combination of two NRTIs, zidovudine and lamivudine (3TC), or placebo. The study had three active arms, A, B and C, in order to identify which components of peri-partum ART were most important. Transmission was lowest in arm A, when all three components of therapy (late prenatal, intra-partum and abbreviated post-partum) were used. Intra-partum therapy alone (arm C) was no more effective than placebo, while intra-partum plus post-partum therapy (arm B) was intermediate in efficacy. Data from PETRA support the use of combination ART in pregnancy. The rate of perinatal HIV transmission with combined zidovudine and lamivudine in PETRA arm B was less than half that of zidovudine monotherapy in a similar population with equivalent drug exposure in the HIVNET 012 trial described below.53,56 Most infants were breastfed in both studies.
The HIVNET 012 study56 showed the superiority of nevirapine, a non-nucleoside analogue HIV-1 reverse transcriptase inhibitor (NNRTI), used intra-partum with a single post-partum dose to the newborn, over zidovudine given intra-partum and for 1 week post-partum. In this Ugandan study, nevirapine was 47% more effective than zidovudine at reducing perinatal HIV transmission. Nevirapine has a long elimination half-life, providing appreciable blood concentrations for up to 1 week after administration. The pharmacokinetics of nevirapine allow very simplified dosing to obtain sustained serum concentrations at a low cost (approximately US$4). An earlier study demonstrated a 1.3 log decrease in plasma HIV viral load 1 week after a single 200 mg nevirapine dose, and substantial (60.5% of plasma) concentrations of nevirapine in breast milk at 1 week.57 In HIVNET 012, the prolonged potent activity of nevirapine enabled a single dose to be given to the newborn under direct observation, whereas the post-partum zidovudine regimen had to be measured out and administered by mothers to the newborn twice a day for 7 days. Therefore, lack of strict adherence to this component of the regimen may have contributed to the superiority of nevirapine over zidovudine. Nevirapine, unlike zidovudine, does not require intracellular phosphorylation to become active against HIV-1 reverse transcriptase. Rapid onset of potent antiretroviral activity may explain the relative advantage of nevirapine over zidovudine initiated once labour has started.56 In that regard, nevirapine may be useful for HIV-infected women who present in labour without previous ART during pregnancy.
Although the results from HIVNET 012 are promising for resource-poor countries, there are some caveats to the widespread adoption of perinatal nevirapine monotherapy. Nevirapine is metabolized via the hepatic cytochrome P450 enzyme pathway. During the initial 2 weeks of therapy, nevirapine induces the activity of these enzymes and thereby alters its plasma concentration until a steady state is achieved. Therefore, if nevirapine is initiated during pregnancy rather than intra-partum as in HIVNET 012, plasma concentrations of the drug in newborns may not be sustained since autoinduction of fetal hepatic metabolism has already taken place.58 In addition, HIV easily develops resistance to nevirapine: a single mutation at one of two primary sites in the reverse transcriptase gene (Y181C or K103N) can reduce the antiretroviral activity of nevirapine.59 Prolonged exposure to low doses of nevirapine during the washout period after a single intra-partum dose has selected for strains of HIV with nevirapine resistance.60 The development of HIV strains resistant to nevirapine may also compromise drug regimens which contain other NNRTIs, such as efavirenz and delavirdine, as these reverse transcriptase mutations often confer cross-resistance. Therefore, if antiretroviral agents that can be combined with nevirapine are readily available, use of nevirapine alone should be discouraged until further resistance data are reported.
In summary, recent prospective clinical trials indicate that: (i) for ART to be effective in prevention of perinatal HIV transmission, it should be started at or before the onset of labour; (ii) breastfeeding can lead to a decrease in response by allowing post-partum transmission to occur; and (iii) combination therapy is superior to monotherapy.
Retrospective clinical trials
A retrospective review of zidovudine use by HIV-seropositive pregnant women in New York State, USA, after the publication of PACTG 076 revealed that, in clinical practice, adherence to the full protocol was often incomplete.11,61 The rate of HIV transmission was 6.1% if therapy was started prenatally, 10.0% if initiated intra-partum, and 5.9% when begun in the newborn within 12 h. However, if zidovudine treatment was begun >48 h after birth, the rate of HIV transmission was 18.4%, which did not differ significantly from the rate in untreated newborns (26.6%). Therefore, as shown in studies conducted in the developing world, an abbreviated peri-partum course of zidovudine retains some of the protective effect of the full PACTG 076 regimen. The efficacy of ART initiated as soon as possible (within a few hours) after birth stresses that a significant proportion of its effect is as post-exposure prophylaxis'; it essentially aborts an infection when a less diverse virus population is present in small numbers and before it can become established in the newborn.16,62
Highly active antiretroviral therapy (HAART), composed of three or more agents including either an HIV-1-specific protease inhibitor or NNRTI, is the current standard of care for treatment of HIV infection.63,64 The most recent guidelines of the USA Public Health Service Task Force recommend a similar approach for the treatment of HIV infection in pregnancy.65 This strategy will lead to maximal viral suppression, more durable efficacy of therapy, delayed development of drug resistance and preserved maternal options for future therapy. Perinatal transmission of ART-resistant HIV has been documented.66 The prevalence of these resistant strains is expected to rise with widespread use of combination therapy and its requirement for strict dosing adherence. As the HIV epidemic advances in women, the potential for increased transmission of drug-resistant virus from mother to child will increase, especially if zidovudine monotherapy is the preferred perinatal regimen. Genotypic or phenotypic viral resistance testing may help guide choice of therapy in newborns as well as in pregnant women who are failing ART or naïve to therapy with recent infection in areas with a high prevalence of resistant HIV.67
The use of HAART in pregnancy has been reported in a number of small series.6870 Low rates (<2%) of perinatal HIV transmission have been observed in >200 pregnant women so treated. We have published outcomes of 30 pregnant HIV-infected women with advanced disease treated with combination ART (including 13 with protease inhibitors) in New York.68 The women had a median CD4+ cell count of 285 (561100) cells/mm3, 53% had AIDS, 37% had evidence of active illicit substance use and 67% had previous ART exposure. None of the 28 infants was infected with HIV (one was lost to follow-up, and one was stillborn). Prospective clinical trials of regimens containing protease inhibitors are in progress. While results of these studies are pending, careful monitoring and reporting of adverse events while on combination therapy and maintenance of antiretroviral pregnancy registries will assist practitioners in making decisions with their patients regarding optimal HIV treatment during pregnancy.
Pharmacokinetic considerations of antiretroviral therapy in pregnancy
Maternal weight may alter the effectiveness of antiretroviral drugs during pregnancy.71 In a substudy of PACTG 076, in which maternal weight was divided into quartiles, it was found that zidovudine use reduced transmission less well in the heaviest women (26% for women >82 kg) than in those in the other three quartiles (79% effective).71 This discrepancy in efficacy may have been a result of weight-related differences in the volume of distribution of zidovudine with altered plasma (and potentially intracellular) concentrations. Fetal concentrations of zidovudine may also depend on on maternal weight since placental transfer of zidovudine is dependent on passive diffusion from the mother.71 Pharmacokinetic studies of ART concentrations during pregnancy are needed to elucidate the potential need for dosing modification based on maternal weight as well as pregnancy-related changes in hepatic drug metabolism, serum protein concentrations, drug absorption and clearance of drug by the placenta and fetus. Before changing dosing, one must consider the potential of increased drug-related toxicity.
Safety of antiretroviral therapy in pregnancy
Exposure of the fetus to antiretroviral agents may have long-term complications. Fetal contact with these agents during the first trimester may occur inadvertently with increased frequency as more HIV-infected women are maintained on combination regimens. More data are needed to establish the safety of these agents to meet the dual goals of protecting the fetus from HIV and avoiding potential late morbidity in those children born uninfected. The most recent interim report from the Antiretroviral Pregnancy Registry in the USA found no increase in birth defects or any specific pattern of birth defect associated with antiretroviral use either with or without first trimester exposure during 860 pregnancies.72 This report included data from 140 pregnancies in which protease inhibitors were used and 19 that included NNRTIs. However, reports from registries such as this are limited because of potential inconsistencies in practitioner reporting, incomplete data and lack of long-term follow-up. Any fetus being exposed to antiretroviral agents should be closely monitored for adverse effects by fetal sonography.
Animal studies have not provided conclusive evidence of specific teratogenicity or carcinogenicity of antiretroviral drugs. All NRTIs cross the placenta in human or animal studies.65 Zidovudine has been associated with noninvasive vaginal tumours in rats and mice after prolonged exposure to high doses.73 Zalcitabine has inhibited normal lymphocyte function and caused thymic lymphomas and hydrocephalus in rodents.65,73 Animal teratogenicity studies with stavudine have been negative, except that decreases in bone calcification have been found in rodents.65 High doses of abacavir have led to anasarca and skeletal malformations in rats.65
Efavirenz, an NNRTI, is not recommended for use during pregnancy because of its association with fetal malformations, including anencephaly, anophthalmia and cleft palate, in cynomolgus monkeys exposed in utero.74 Delavirdine, another NNRTI, has caused ventricular septal defects in rodents.65 Use of indinavir, a protease inhibitor, can lead to indirect hyperbilirubinaemia, which may have adverse effects in newborns.73 Cryptorchidism in rodents has been noted with ritonavir.65 Amprenavir, a protease inhibitor licensed recently for use in the USA, has been associated with low body weight, bone ossification defects and thymic abnormalities in rabbits and rats.65
Animal teratogenicity studies on other available drugs [NRTIs (didanosine, lamivudine), an NNRTI (nevirapine) and protease inhibitors (saquinavir, nelfinavir)] are negative. Teratogenicity studies in humans are not available for any of the currently available antiretrovirals. Long-term animal carcinogenicity studies are chiefly incomplete.
Pregnant women are prone to hyperglycaemia and some develop frank gestational diabetes. Protease inhibitors have been linked with degrees of glucose intolerance, ranging from mild hyperglycaemia to ketoacidosis,75 so, pregnant women receiving combination therapy with a protease inhibitor should be monitored closely for signs and symptoms of elevated glucose.
The Swiss Neonatal HIV Study reported the outcome of 37 women treated with combination ART: 21 with dual NRTI therapy and 16 with regimens including a protease inhibitor.76 Twenty-nine of the 37 women had some adverse event reported, chiefly anaemia (in 42%) associated with the combination of zidovudine and lamivudine. The most common adverse neonatal outcome was prematurity below 37 weeks' gestation in 33%, which differed significantly from the rates seen in the same population with zidovudine monotherapy (17%) and those who received no ART (14%). One case of extrahepatic biliary atresia in an infant exposed to indinavir was considered to be possibly drug related. Our experience with 30 HIV-infected pregnant women in New York on combination ART, including 13 taking protease inhibitors, demonstrated fewer adverse outcomes than the Swiss cohort.68 Maternal complications included four cases of hypertension, one of gestational diabetes and one exacerbation of chronic hepatitis C. Newborn adverse events included one stillbirth, one case of microcephaly and five infants weighing <2500 g, including the only two babies (7%) born prematurely. Median birthweight was not affected by maternal protease inhibitor use. Preliminary data from a large review of perinatal ART use by 462 women in the USA in which 25% received zidovudine monotherapy, 36% protease inhibitor-containing regimens and 70% combination therapy revealed no association of protease inhibitor use with prematurity, low birth weight, stillbirth or malformation.70
Of concern is a recent French report of possible mitochondrial toxicity related to zidovudine and lamivudine combination therapy.77 Significantly higher concentrations of zidovudine are required to inhibit human DNA polymerases than HIV RNA-dependent DNA polymerase; however, mitochondrial DNA polymerase may be inhibited at concentrations near those achieved with standard zidovudine dosing.78 Cardiac and hepatic tissue may be affected disproportionately, because of their high mitochondrial content.73 The French report77 noted that of 1754 children exposed to perinatal ART (mostly zidovudine), five developed late (414 months of age) neurological symptoms (two of these five died) and three were asymptomatic but had elevated lactate and/or liver/pancreatic enzyme abnormalities; none was HIV infected. The atypical and varied presentations of these cases raise doubts about the causative role of mitochondrial toxicity.79 A recent American review of NIH and CDC databases of the children of >20000 HIV-infected mothers revealed no deaths attributable to mitochondrial toxicity among those exposed perinatally to NRTI and HIV uninfected.80 Further information is required before recommendations can be made about mitochondrial toxicity and perinatal ART use.
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General principles of antiretroviral therapy use during pregnancy |
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HIV-infected pregnant women who are not currently on ART should start therapy after the first trimester (14 weeks' gestation) based on the same criteria and guidelines used for non-pregnant patients.65 For example, consideration is given to the woman's willingness to start therapy, her HIV viral load, CD4+ cell count, and history and future risk of opportunistic infections. A major goal of HIV therapy in pregnancy is to improve maternal health by providing durable suppression of HIV while maintaining future therapeutic options. Combination ART is usually required to achieve this outcome. Zidovudine, if appropriate (based on previous antiretroviral exposure, drug resistance testing or tolerability) should be part of maternal therapy. Regardless of zidovudine use before birth, zidovudine should be given during labour and included in the regimen of the newborn. Combination therapy with zidovudine, lamivudine and/or nevirapine may also be considered for intra-partum use, especially in HIV-infected women who present in labour. If therapy is interrupted at any time during pregnancy, all antiretrovirals should be started and stopped together. Women already on ART who present during the first trimester may choose either to continue or to stop therapy and restart at 14 weeks' gestation after a discussion of risks and benefits.
Potential drug interactions between non-HIV drugs and antiretrovirals, such as the reduction in methadone concentrations with nevirapine, should be taken into consideration because of their possible effect on efficacy and adherence. Appropriate prophylaxis of HIV-related opportunistic infections81 should be provided to HIV-infected pregnant women.
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Strategies to prevent perinatal HIV transmission without the use of antiretroviral therapy |
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The use of antiseptic vaginal and cervical washes has been suggested as an inexpensive way to reduce potential viral exposure to newborns during delivery. Chlorhexidine has had widespread use as a disinfectant and can inhibit HIV viral replication in vitro at concentrations of 0.2%.87 A clinical trial in Africa of 0.25% chlorhexidine for vaginal and newborn washing did not reduce HIV transmission, however.88 Studies are under way to assess the benefit of chlorhexidine at higher concentrations.8
Screening and treatment for genital ulcer diseases, such as syphilis, in HIV-infected pregnant women can be of dual benefit to the newborn by reducing the risk of acquiring the sexually transmitted disease as well as transmission of HIV.27
In industrialized countries, HIV-infected women are strongly discouraged to breastfeed to prevent post-partum transmission of HIV. The widespread applicability of such an approach in developing countries is more problematical. Nduati and colleagues89 conducted a randomized clinical trial in Kenya comparing the incidence of infant HIV infection and mortality in the first 2 years of life in breastfed and formula-fed infants. There was significantly more infant HIV-1 infection in the breastfeeding arm (cumulative probability of HIV infection of 36.7%) than in the formula-fed arm (20.5%). Most motherchild HIV transmission from breastfeeding was noted in the first 2 months of infant life. Since significant numbers of women (30%) in the formula group breastfed at least once, the rate of breast milk transmission of HIV was likely to be even higher. There are tremendous societal pressures for women to breastfeed in developing countries. Women who choose to feed with formula face the risk of being ostracized, because it may be seen as a sign that they are HIV infected. Although HIV transmission rates were strikingly different in the two groups, the 2 year mortality rate was 20% with formula and 24.4% with breastfeeding (P = 0.3).89 If formula feeding is to be substituted for breastfeeding in HIV-infected women in the developing world, then it is essential that: (i) clean water is readily available; (ii) formula feeds are affordable; (iii) social support networks exist for women who use formula; and (iv) treatment for diarrhoeal diseases can be freely administered.
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Conclusions |
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Whilst tremendous progress has been made in this aspect of the HIV epidemic, much more work is needed not only to protect infants from infection with HIV but to ensure that they remain healthy after interventions, and to provide access to treatment for their parents so they will not be orphaned. This will require planning and the expenditure of resources with the same dedication that is deployed to wage military wars.
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Notes |
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References |
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2 . UNAIDS/WHO. (2000). Report on the global HIV/AIDS epidemic, June, 2000. [Online.] http://www.unaids.org/epidemic_update/report/. [2 July 2000, last date accessed.]
3 . Centers for Disease Control and Prevention. (1998). Critical need to pay attention to HIV prevention for women: minority and young women bear greatest burden. CDC Update, 14.
4
.
Palella, F. J., Delaney, K. M., Moorman, A. C., Loveless, M. O., Fuhrer, J., Satten, G. A. et al. (1998). Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. New England Journal of Medicine 338, 85360.
5
.
Connor, E. M., Sperling, R. S., Gelber, R., Kiselev, P., Scott, G., O'sullivan, M. J. et al. (1994). Reduction of maternalinfant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. New England Journal of Medicine 331, 117380.
6 . Susser, M. (1998). The prevention of perinatal HIV transmission in the less-developed world. American Journal of Public Health 88, 5478.[ISI][Medline]
7 . Mofenson, L. M. (1997). Interaction between timing of perinatal human immunodeficiency virus infection and the design of preventive and therapeutic interventions. Acta Paediatrica 421, Suppl., 19.
8 . Stringer, J. S. & Vermund, S. H. (1999). Prevention of mother-to-child transmission of HIV-1. Current Opinion in Obstetrics and Gynecology 11, 42734.[Medline]
9 . Bertolli, J., St Louis, M. E., Simonds, R. J., Nieburg, P., Kamenga, M., Brown, C. et al. (1996). Estimating the timing of mother-to-child transmission of human immunodeficiency virus in a breast-feeding population in Kinshasa, Zaire. Journal of Infectious Diseases 174, 7226.[ISI][Medline]
10 . Chouquet, C., Burgard, M., Richardson, S., Rouzioux, C. & Costagliola, D. (1997). Timing of mother-to-child HIV-1 transmission and diagnosis of infection based on polymerase chain reaction in the neonatal period by a non-parametric method. AIDS 11, 11834.[ISI][Medline]
11
.
Wade, N. A., Birkhead, G. S., Warren, B. L., Charbonneau, T. T., French, P. T., Wang, L. et al. (1998). Abbreviated regimens of zidovudine prophylaxis and perinatal transmission of the human immunodeficiency virus. New England Journal of Medicine 339, 140914.
12 . The European Mode of Delivery Collaboration. (1999). Elective caesarean-section versus vaginal delivery in prevention of vertical HIV-1 transmission: a randomised clinical trial. Lancet 353, 10359.[ISI][Medline]
13 . The Working Group on Mother-to-Child Transmission of HIV. (1995). Rates of mother-to-child transmission of HIV-1 in Africa, America, and Europe: results from 13 perinatal studies. Journal of Acquired Immune Deficiency Syndromes 8, 50610.
14 . Dickover, R. E., Garratty, E. M., Herman, S. A., Sim, M. S., Plaeger, S., Boyer, P. J. et al. (1996). Identification of levels of maternal HIV-1 RNA associated with risk of perinatal transmission. Effect of maternal zidovudine treatment on viral load. Journal of the American Medical Association 275, 599605.[Abstract]
15
.
Mofenson, L. M., Lambert, J. S., Stiehm, E. R., Bethel, J., Meyer, W. A., Whitehouse, J. et al. (1999). Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated with zidovudine. Pediatric AIDS Clinical Trials Group Study 185 Team. New England Journal of Medicine 341, 38593.
16 . Jansson, M., Orlandi, P., Scarlatti, G., Moschese, V., Romiti, M. L., Cancrini, C. et al. (1997). Role of immunity in maternalinfant HIV-1 transmission. Acta Paediatrica 421, Suppl., 3945.
17
.
Sperling, R. S., Shapiro, D. E., Coombs, R. W., Todd, J. A., Herman, S. A., McSherry, G. D. et al. (1996). Maternal viral load, zidovudine treatment, and the risk of transmission of human immunodeficiency virus type 1 from mother to infant. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. New England Journal of Medicine 335, 16219.
18 . Cao, Y., Krogstad, P., Korber, B. T., Koup, R. A., Muldoon, M., Macken, C. et al. (1997). Maternal HIV-1 viral load and vertical transmission of infection: the Ariel Project for the prevention of HIV transmission from mother to infant. Nature Medicine 3, 54952.[ISI][Medline]
19
.
Garcia, P. M., Kalish, L. A., Pitt, J., Minkoff, H., Quinn, T. C., Burchett, S. K. et al. (1999). Maternal levels of plasma human immunodeficiency virus type 1 RNA and the risk of perinatal transmission. Women and Infants Transmission Study Group. New England Journal of Medicine 341, 394402.
20
.
Cardo, D. M., Culver, D. H., Ciesielski, C. A., Srivastava, P. U., Marcus, R., Abiteboul, D. et al. (1997). A casecontrol study of HIV seroconversion in health care workers after percutaneous exposures. Centers for Disease Control and Prevention Needlestick Surveillance Group. New England Journal of Medicine 337, 148590.
21 . John, G. C., Nduati, R. W., Mbori-Ngacha, D., Overbaugh, J., Welch, M., Richardson, B. A. et al. (1997). Genital shedding of human immunodeficiency virus type 1 DNA during pregnancy: association with immunosuppression, abnormal cervical or vaginal delivery discharge, and severe vitamin A deficiency. Journal of Infectious Diseases 175, 5762.[ISI][Medline]
22 . Boyer, P. J., Dillon, M., Navaie, M., Deveikis, A., Keller, M., ORourke, S. et al. (1994). Factors predictive of maternalfetal transmission of HIV-1. Preliminary analysis of ziduvodine given during pregnancy and/or delivery. Journal of the American Medical Association 271, 192530.[Abstract]
23
.
Landesman, S. H., Kalish, L. A., Burns, D. N., Minkoff, H., Fox, H. E., Zorrilla, C. et al. (1996). Obstetrical factors and the transmission of human immunodeficiency virus type 1 from mother to child. The Women and Infants Transmission Study. New England Journal of Medicine 334, 161723.
24 . Kuhn, L., Steketee, R. W., Weedon, J., Abrams, E. J., Lambert, G., Bamji, M. et al. (1999). Distinct risk factors for intrauterine and intra-partum human immunodeficiency virus transmission and consequences for disease progression in infected children. Perinatal AIDS Collaborative Transmission Study. Journal of Infectious Diseases 179, 528.[ISI][Medline]
25 . Van Dyke, R. B., Korber, B. T., Popek, E., Macken, C., Widmayer, S. M., Bardeguez, A. et al. (1999). The Ariel Project: a prospective cohort study of maternalchild transmission of human immunodeficiency virus type 1 in the era of maternal antiretroviral therapy. Journal of Infectious Diseases 179, 31928.[ISI][Medline]
26 . Wabwire-Mangen, F., Gray, R. H., Mmiro, F. A., Ndugwa, C., Abramowsky, C., Wabinga, H. et al. (1999). Placental membrane inflammation and risks of maternal-to-child transmission of HIV-1 in Uganda. Journal of Acquired Immune Deficiency Syndromes 22, 37985.[ISI][Medline]
27 . Lee, M. J., Hallmark, R. J., Frenkel, L. M. & Del Priore, G. (1998). Maternal syphilis and vertical perinatal transmission of human immunodeficiency virus type-1 infection. International Journal of Gynaecology and Obstetrics 63, 24752.[Medline]
28 . Chuachoowong, R., Shaffer, N., Siriwasin, W., Chaisilwattana, P., Young, N. L., Mock, P. A. et al. (2000). Short-course antenatal zidovudine reduces both cervicovaginal human immunodeficiency virus type 1 RNA levels and risk of perinatal transmission. Bangkok Collaborative Perinatal HIV Transmission Study Group. Journal of Infectious Diseases 181, 99106.[ISI][Medline]
29 . Kreiss, J. (1997). Breast feeding and vertical transmission of HIV-1. Acta Paediatrica 421, Suppl., 1137.
30 . Dunn, D. T., Newell, M. L., Ades, A. E. & Peckham, C. S. (1992). Risk of human immunodeficiency virus type 1 transmission through breastfeeding. Lancet 340, 5858.[ISI][Medline]
31 . Leroy, V., Newell, M. L., Dabis, F., Peckham, C., Van de Perre, P., Bulterys, M. et al. (1998). International multicentre pooled analysis of late postnatal mother-to-child transmission of HIV-1 infection. Ghent International Working Group on Mother-to-Child Transmission of HIV. Lancet 352, 597600.[ISI][Medline]
32 . Nduati, R. W., John, G. C., Richardson, B. A., Overbaugh, J., Welch, M., Ndinya-Achola, J. et al. (1995). Human immunodeficiency virus type 1-infected cells in breast milk: association with immunosuppression and vitamin A deficiency. Journal of Infectious Diseases 172, 14618.[ISI][Medline]
33 . Semba, R. D., Kumwenda, N., Hoover, D. R., Taha, T. E., Quinn, T. C., Mtimavalye, L. et al. (1999). Human immunodeficiency virus load in breast milk, mastitis, and mother-to-child transmission of human immunodeficiency virus type 1. Journal of Infectious Diseases 180, 938.[ISI][Medline]
34 . Swart, P. J., Kuipers, M. E., Smit, C., Pauwels, R., de Bethune, M. P., de Clercq, E. et al. (1996). Antiviral effects of milk proteins: acylation results in polyanionic compounds with potent activity against human immunodeficiency virus types 1 and 2 in vitro. AIDS Research and Human Retroviruses 12, 76975.[ISI][Medline]
35 . Becquart, P., Hocini, H., Levy, M., Sepou, A., Kazatchkine, M. D. & Belec, L. (2000). Secretory anti-human immunodeficiency virus (HIV) antibodies in colostrum and breast milk are not a major determinant of the protection of early postnatal transmission of HIV. Journal of Infectious Diseases 181, 5329.[ISI][Medline]
36 . Kuhn, L., Coutsoudis, A., Moodley, D., Trabattoni, D., Mngqundaniso, N., Shearer, G. M. et al. (2000). HIV-1-specific T-helper cell responses detected at birth. In Program and Abstracts of the Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, 2000. Abstract 702, p. 206. Foundation for Retrovirology and Human Health, Alexandria, VA.
37 . Semba, R. D. (1997). Overview of the potential role of vitamin A in mother-to-child transmission of HIV-1. Acta Paediatrica 421, Suppl., 10712.
38 . Burns, D. N., FitzGerald, G., Semba, R., Hershow, R., Zorrilla, C., Pitt, J. et al. (1999). Vitamin A deficiency and other nutritional indices during pregnancy in human immunodeficiency virus infection: prevalence, clinical correlates, and outcome. Clinical Infectious Diseases 29, 32834.[ISI][Medline]
39 . Kennedy, C. M., Coutsoudis, A., Kuhn, L., Pillay, K., Mburu, A., Stein, Z. et al. (2000). Randomized controlled trial assessing the effect of vitamin A supplementation on maternal morbidity during pregnancy and post-partum among HIV-infected women. Journal of Acquired Immune Deficiency Syndromes 24, 3744.[ISI][Medline]
40 . Rodriguez, E. M., Mofenson, L. M., Chang, B. H., Rich, K. C., Fowler, M. G., Smeriglio, V. et al. (1996). Association of maternal drug use during pregnancy with maternal HIV culture positivity and perinatal transmission. AIDS 10, 27382.[ISI][Medline]
41 . Burns, D. N., Landesman, S., Muenz, L. R., Nugent, R. P., Goedert, J. J., Minkoff, H. et al. (1994). Cigarette smoking, premature rupture of membranes, and vertical transmission of HIV-1 among women with low CD4+ levels. Journal of Acquired Immune Deficiency Syndromes 7, 71826.[Medline]
42 . Moore, J. P., Trkola, A. & Dragic, T. (1997). Co-receptors for HIV-1 entry. Current Opinion in Immunology 9, 55162.[ISI][Medline]
43 . Samson, M., Libert, F., Doranz, B. J., Rucker, J., Liesnard, C., Farber, C. M. et al. (1996). Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 382, 7225.[ISI][Medline]
44 . Liu, R., Paxton, W. A., Choe, S., Ceradini, D., Martin, S. R., Horuk, R. et al. (1996). Homozygous defect in HIV-1 co-receptor accounts for resistance for some multiply-exposed individuals to HIV-1 infection. Cell 86, 36777.[ISI][Medline]
45
.
Kostrikis, L. G., Neumann, A. U., Thomson, B., Korber, B. T., McHardy, P., Karanicolas, R. et al. (1999). A polymorphism in the regulatory region of the CC-chemokine receptor 5 gene influences perinatal transmission of human immunodeficiency virus type 1 to African-American infants. Journal of Virology 73, 1026471.
46 . Philpott, S., Burger, H., Charbonneau, T., Grimson, R., Vermund, S. H., Visosky, A. et al. (1999). CCR5 genotype and resistance to vertical transmission of HIV-1. Journal of Acquired Immune Deficiency Syndromes 21, 18993.[ISI][Medline]
47 . Stiehm, E. R., Lambert, J. S., Mofenson, L. M., Bethel, J., Whitehouse, J., Nugent, R. et al. (1999). Efficacy of zidovudine and human immunodeficiency virus (HIV) hyperimmune immunoglobulin for reducing perinatal HIV transmission from HIV-infected women with advanced disease: results of Pediatric AIDS Clinical Trials Group Protocol 185. Journal of Infectious Diseases 179, 56775.[ISI][Medline]
48 . Ugen, K. E., Srikantan, V., Goedert, J. J., Nelson, R. P., Williams, W. V. & Weiner, D. B. (1997). Vertical transmission of human immunodeficiency virus type 1: seroreactivity by maternal antibodies to the carboxy region of the gp41 envelope glycoprotein. Journal of Infectious Diseases 175, 639.[ISI][Medline]
49 . Van Rompay, K. K., Berardi, C. J., Dillard-Telm, S., Tarara, R. P., Canfield, D. R., Valverde, C. R. et al. (1998). Passive immunization of newborn rhesus macaques prevents oral simian immunodeficiency virus infection. Journal of Infectious Diseases 177, 124759.[ISI][Medline]
50 . Siegel, F., Kurth, R. & Norley, S. (1995). Neither whole inactivated virus immunogen nor passive immunoglobulin transfer protects against SIVagm infection in the African green monkey natural host. Journal of Acquired Immune Deficiency Syndromes 8, 21726.
51 . Shaffer, N., Chuachoowong, R., Mock, P. A., Bhadrakom, C., Siriwasin, W., Young, N. L. et al. (1999). Short-course zidovudine for perinatal HIV-1 transmission in Bangkok, Thailand: a randomised controlled trial. Bangkok Collaborative Perinatal HIV Transmission Study Group. Lancet 353, 77380.[ISI][Medline]
52 . Wiktor, S. Z., Ekpini, E., Karon, J. M., Nkengasong, J., Maurice, C., Severin, S. T. et al. (1999). Short-course oral zidovudine for prevention of mother-to-child transmission of HIV-1 in Abidjan, Côte d'Ivoire: a randomised trial. Lancet 353, 7815.[ISI][Medline]
53 . Dabis, F., Msellati, P., Meda, N., Welffens-Ekra, C., You, B., Manigart, O. et al. (1999). Six-month efficacy, tolerence, and acceptability of a short regimen of oral zidovudine to reduce vertical transmission of HIV in breastfed children in Côte d'Ivoire and Burkina Faso: a double-blind placebo-controlled multicentre trial. DITRANE Study Group. Diminution de la Transmission MèreEnfant. Lancet 353, 78692.[ISI][Medline]
54 . Dorenbaum, A., Rodman, J. H., Mirochnick, M., Hernandez, J., Fridland, A. & ACTG 324 Team. (2000). Systemic pharmacokinetics of oral zidovudine given during labor and delivery to HIV-1-infected pregnant women. In Program and Abstracts of the Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, 2000. Abstract 660, p. 199. Foundation for Retrovirology and Human Health, Alexandria, VA.
55 . Saba, J. (1999). The results of the PETRA intervention trial to prevent perinatal transmission in sub-Saharan Africa. Presented at the Sixth Conference on Retroviruses and Opportunistic Infections, Chicago, IL, 1999. [Online.] http://www.retroconference.org/99/ lect_symposia/sym_session8.html. [30 June 2000, date last accessed.]
56 . Guay, L. A., Musoke, P., Fleming, T., Bagenda, D., Allen, M., Nakabiito, C. et al. (1999). Intra-partum 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 354, 795802.[ISI][Medline]
57 . Musoke, P., Guay, L. A., Bagenda, D., Mirochnick, M., Nakabiito, C., Fleming, T. et al. (1999). 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 13, 47986.[ISI][Medline]
58 . Mirochnick, M., Siminski, S., Fenton, T., Sullivan, J. & the PACTG 250 Protocol Team. (2000). Pharmacokinetics of nevirapine in pregnant women and in their infants following in utero exposure. In Program and Abstracts of the Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, 2000. Abstract 716, p. 209. Foundation for Retrovirology and Human Health, Alexandria, VA.
59 . Richman, D. D., Havlir, D., Corbeil, J., Looney, D., Ignacio, C., Spector, S. A. et al. (1994). Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. Journal of Virology 68, 16606.[Abstract]
60 . Becker-Pergola, G., Guay, L. A., Mmiro, F. A., Musoke, P., Fung, S., Jackson, J. B. et al. (2000). Selection of the K103N nevirapine resistance mutation in Ugandan women receiving NVP prophylaxis to prevent HIV-1 vertical transmission (HIVNET-006). In Program and Abstracts of the Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, 2000. Abstract 658, p. 198. Foundation for Retrovirology and Human Health, Alexandria, VA.
61 . Shaffer, N., Bulterys, M. & Simonds, R. J. (1999). Short courses of zidovudine and perinatal transmission of HIV. New England Journal of Medicine 340, 10423.[ISI][Medline]
62 . Dickover, R., Garratty, E., Plaeger, S. & Bryson, Y. (2000). Perinatal transmission of major, minor, and multiple HIV-1 strains in utero and intra-partum. In Program and Abstracts of the Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, 2000. Abstract 181, p. 109. Foundation for Retrovirology and Human Health, Alexandria, VA.
63 . Centers for Disease Control. (1998). Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Department of Health and Human Services and Henry J. Kaiger Family Foundation. Morbidity and Mortality Weekly Report 47, 4382.
64 . Gazzard, B. & Moyle, G. (1998). 1998 revision to the British HIV Association guidelines for antiretroviral treatment of HIV seropositive individuals. BHIVA Guidelines Writing Committee. Lancet 352, 3146.[ISI][Medline]
65 . US Public Health Service Perinatal HIV Guidelines Working Group. (2000). US Public Health Service Task Force recommendations for the use of antiretroviral drugs in pregnant women infected with HIV-1 for maternal health and for reducing perinatal HIV-1 transmission in the United States. [Online.] http://hivatis.org/ guidelines/perinatal/PerinatalFeb2500.pdf. [1 March 2000, last date accessed.]
66 . Frenkel, L. M., Wagner, L. E., Demeter, L. M., Dewhurst, S., Coombs, R. W., Murante, B. L. et al. (1995). Effects of zidovudine use during pregnancy on resistance and vertical transmission of human immunodeficiency virus type 1. Clinical Infectious Diseases 20, 13216.[ISI][Medline]
67
.
Hirsch, M. S., Brun-Vezinet, F., d'Aquila, R. T., Hammer, S. M., Johnson, V. A., Kuritzkes, D. R. et al. (2000). Antiretroviral drug resistance testing in adult HIV-1 infection: recommendations of an International AIDS SocietyUSA Panel. Journal of the American Medical Association 283, 241726.
68
.
McGowan, J. P., Crane, M., Wiznia, A. A. & Blum, S. (1999). Combination antiretroviral therapy in human immunodeficiency virus-infected pregnant women. Obstetrics and Gynecology 94, 6416.
69 . Morris, A., Zorrilla, C., Vajaranant, M., Dobles, A., Cu-uvin, S., Jones, T. et al. (1999). A review of protease inhibitor use in 89 pregnancies. In Program and Abstracts of the Sixth Conference on Retroviruses and Opportunistic Infections, Chicago, IL, 1999. Abstract 686, p. 197. Foundation for Retrovirology and Human Health, Alexandria, VA.
70 . Shapiro, D., Tuomala, R., Samelson, R., Burchett, S., Ciupak, G., McNamara, J. et al. (2000). Ante-partum antiretroviral therapy and pregnancy outcomes in 462 HIV-infected women in 19981999. In Program and Abstracts of the Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, 2000. Abstract 664, p. 199. Foundation for Retrovirology and Human Health, Alexandria, VA.
71
.
Shapiro, D. E., Sperling, R. S., Mandelbrot, L., Britto, P. & Cunningham, B. E. (1999). Risk factors for perinatal human immunodeficiency virus transmission in patients receiving zidovudine prophylaxis. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. Obstetrics and Gynecology 94, 897908.
72 . PharmaResearch Corp. (1999). The Antiretroviral Therapy Pregnancy Registry Interim Report: July 31, 1999. The Antiretroviral Pregnancy Registry, Wilmington, NC.
73 . Minkoff, H. & Augenbraun, M. (1997). Antiretroviral therapy for pregnant women. American Journal of Obstetrics and Gynecology 176, 47889.[ISI][Medline]
74 . DuPont Pharmaceuticals. (1998). Sustiva (efavirenz) package insert. Wilmington, DE.
75 . Food and Drug Administration. (1997). FDA Public Health Advisory: Reports of Diabetes and Hyperglycemia in Patients Receiving Protease Inhibitors for Treatment of Human Immunodeficiency Virus (HIV). Food and Drug Administration, US Public Health Service, Department of Health and Human Services, Rockville, MD.
76 . Lorenzi, P., Spicher, V. M., Laubereau, B., Hirschel, B., Kind, C., Rudin, C. et al. (1998). Antiretroviral therapies in pregnancy: maternal, fetal and neonatal effects. Swiss HIV Cohort Study, the Swiss Collaborative HIV and Pregnancy Study, and the Swiss Neonatal HIV Study. AIDS 12, F2417.[ISI][Medline]
77 . Blanche, S., Tardieu, M., Rustin, P., Slama, A., Barret, B., Firtion, G. et al. (1999). Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet 354, 10849.[ISI][Medline]
78 . Centers for Disease Control. (1994). CDC recommendations of the U.S. Public Health Service task force on the use of zidovudine to reduce perinatal transmission of human immunodeficiency virus. Morbidity and Mortality Weekly Report 43, 121.
79 . Morris, A. A. & Carr, A. (1999). HIV nucleoside analogues: new adverse effects on mitochondria? Lancet 354, 10467.[ISI][Medline]
80 . McIntosh, K. (2000). Mitochondrial toxicity of perinatally administered zidovudine. In Program and Abstracts of the Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, 2000. Abstract S14, p. 242. Foundation for Retrovirology and Human Health, Alexandria, VA.
81 . Centers for Disease Control and Prevention. (1999). 1999 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. US Public Health Service and Infectious Diseases Society of America. Morbidity and Mortality Weekly Report 48, 166.
82
.
The International Perinatal HIV Group. (1999). The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1a meta-analysis of 15 prospective cohort studies. New England Journal of Medicine 340, 97787.
83 . Kind, C., Rudin, C., Siegrist, C. A., Wyler, C. A., Biedermann, K., Lauper, U. et al. (1998). Prevention of vertical HIV transmission: additive protective effect of elective Cesarean section and zidovudine prophylaxis. Swiss Neonatal HIV Study Group. AIDS 12, 20510.[ISI][Medline]
84
.
Mandelbrot, L., Le Chenadec, J., Berrebi, A., Bongain, A., Benifla, J. L., del Fraissy, J. F. et al. (1998). Perinatal HIV-1 transmission: interaction between zidovudine prophylaxis and mode of delivery in the French Perinatal Cohort. Journal of the American Medical Association 280, 5560.
85 . Towers, C. V., Deveikis, A., Asrat, T., Major, C. & Nageotte, M. P. (1998). A bloodless cesarean section and perinatal transmission of the human immunodeficiency virus. American Journal of Obstetrics and Gynecology 179, 70814.[ISI][Medline]
86 . Semprini, A. E., Castagna, C., Ravizza, M., Fiore, S., Savasi, V., Muggiasca, M. L. et al. (1995). The incidence of complications after caesarean section in 156 HIV-positive women. AIDS 9, 9137.[ISI][Medline]
87 . Harrison, C. & Chantler, E. (1998). The effect of nonoxynol-9 and chlorhexidine on HIV and sperm in vitro. International Journal of STD and AIDS 9, 927.[Medline]
88 . Biggar, R. J., Miotti, P. G., Taha, T. E., Mtimavalye, L., Broadhead, R., Justesen, A. et al. (1996). Perinatal intervention trial in Africa: effect of a birth canal cleansing intervention to prevent HIV transmission. Lancet 347, 164750.[ISI][Medline]
89
.
Nduati, R., John, G., Mbori-Ngacha, D., Richardson, B., Overbaugh, J., Mwatha, A. et al. (2000). Effect of breastfeeding and formula feeding on transmission of HIV-1: a randomized clinical trial. Journal of the American Medical Association 283, 116774.
Received 20 March 2000; returned 22 June 2000; revised 7 July 2000; accepted 20 July 2000