Advances in prevention of mother-to-child HIV transmission. Rongkavilit C, Asmar BasimI - Indian J Pediatr
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ORIGINAL ARTICLE
Year : 2004 | Volume : 71 | Issue : 1 | Page : 69-79
Advances in prevention of mother-to-child HIV transmission.
Rongkavilit C, Asmar BasimI
Division of Pediatric Infectious Diseases, Children's Hospital of Michigan, Department of Pediatrics, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Correspondence Address:
Division of Pediatric Infectious Diseases, Children's Hospital of Michigan, Department of Pediatrics, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
crongkav@dmc.org
» Abstract
Advances have been made in the understanding of the pathogenesis of mother-to-child transmission of human immunodeficiency virus (HIV). Most transmission occurs during delivery and after birth throught breastfeeding. For this reason, efforts to interrupt transmission have focused on peripartum period and infant feeding. This includes the use of antiretroviral therapy, elective cesarean section and avoidance of breastfeeding. This review summarizes recent major studies and new development on the prevention of mother-to-child HIV transmission. The application and the impact of such interventions in developing world is discussed. Prevention of mother-to-child transmission of HIV should now be integrated as part of basic maternal and child health services in developing countries.
How to cite this article:
Rongkavilit C, Asmar BI. Advances in prevention of mother-to-child HIV transmission. Indian J Pediatr 2004;71:69-79
How to cite this URL:
Rongkavilit C, Asmar BI. Advances in prevention of mother-to-child HIV transmission. Indian J Pediatr [serial online] 2004 [cited 2005 Dec 28];71:69-79. Available from: http://www.ijppediatricsindia.org/article.asp?issn=0019-5456;year=2004;volume=71;issue=1;spage=69;epage=79;aulast=Rongkavilit
Human immunodeficiency virus (HIV) infection is spreading rapidly in women of childbearing age worldwide. Women of childbearing age constitute nearly half of the adults currently living with HIV globally. [1] The epidemic of HIV in women of this age group signifies a serious threat to children. The World Health Organization has estimated that there were approximately 800,000 newly infected children in the year 2002, the majority of whom acquired the infection vertically from their mothers. [1] The developing countries, those with the least available resources, have been the most severely affected by the burden of the HIV pandemic. The increasing number of HIV-infected adults, particularly women, makes the prevention of mother-to-child transmission of HIV a public health priority in many developing countries.
» Risk Factors for Mother-to-child HIV Transmission
HIV transmission from a pregnant woman to her infant mostly takes place at around the time of birth. [2] , [3] Interventions to interrupt transmission at the time of delivery, such as antiretroviral prophylaxis given in late gestation or peripartum and elective cesarean section, have been shown to be effective in reducing perinatal HIV transmission.
There are multiple risk factors that affect perinatal transmission of HIV [Table - 1] . Maternal plasma HIV RNA copy number, also known as HIV viral load, appears to be among the important risk factors for peri­natal transmission of HIV. [4] , [5] , [6] , [7] , [8] , [9] However, although higher plasma HIV RNA levels have been noted among women who transmitted the virus to their infants, overlap in HIV RNA levels has been observed in women who trans­mitted and those who did not transmitted the virus. [4] , [7] Despite the fact that the risk for perinatal transmission of HIV in women with plasma HIV RNA below the detectable level appears to be extremely low, transmission has been reported across the entire range of HIV RNA levels. The HIV RNA threshold below which there is no risk for transmission has not been identified. [4] , [7] Nevertheless, antiretroviral prophylaxis has been shown to be effective in reducing transmission regardless of maternal HIV RNA levels. Since transmission can occur even at low or undetectable HIV RNA copy numbers, HIV RNA levels should not be a determining factor when deciding whether to use antiretroviral prophylaxis.
Levels of HIV in maternal genital tract secretion may affect perinatal transmission. [9] , [10] Previous studies, demonstrating that risk of perinatal HIV transmission is increased in vaginal as compared with elective cesarean deliveries, following prolonged rupture of amniotic membranes, and among first-born twins, suggest that exposure to infected secretions in the birth canal influences transmission. [11] , [12] , [13] Although there is a general correlation between viral load in plasma and in genital secretion, discordance has also been observed. [14] , [15] In the short-course zidovudine (ZDV) trial in Thailand, plasma and cervicovaginal HIV RNA levels were reduced by ZDV treatment, and each independently correlated with the risk of perinatal HIV transmission. [10]
Decreased CD4+ T-lymphocyte counts are an indicator of worsening immune deficiency and have been associated with increased perinatal HIV transmission. [6] However, a low CD4+ T-lymphocyte count may be a result of a high plasma HIV RNA level and, therefore, may not be an independent risk factor for perinatal transmission of HIV.
Vitamin A deficiency and malnutrition can worsen immune deficiency and can cause disruption of mucosal integrity both of which are associated with increased perinatal HIV transmission. However, an analysis of a randomized trial in South Africa concluded that vitamin A supplementation lacked efficacy in preventing perinatal HIV transmission. [16] Interestingly, the women receiving vitamin A in this trial were less likely to have a premature delivery, but this was not observed in the Tanzania trial. [17] Among the preterm infants in the South African trial, those whose mothers received vitamin A were less likely to be infected than those in the placebo group.
Maternal use of illicit drugs such as cocaine and heroin has been associated with a risk up to three-fold higher of transmitting HIV to the infants. [18] Cigarette smoking during pregnancy may also increase the risk of transmission. [19] Discontinuing these practices during pregnancy might reduce the risk of perinatal HIV transmission.
» Antiretroviral prophylaxis to prevent mother-to-child HIV transmission
Recent randomized clinical trials have assessed the efficacy of a number of antiretroviral interventions [Table - 2] . This article will discuss as the results of the published clinical trials in non-breastfeeding and breastfeeding populations. When possible, observational comparisons between the trials will be made to provide ways to better understand and strengthen mother-to-child HIV prevention strategies.
» Clinical trials of antiretroviral prophylaxis in non-breastfeeding populations
In 1994, the Pediatric AIDS Clinical Trials Group (PACTG) Protocol 076, conducted in the United States and France, demonstrated the effectiveness of antire­troviral therapy for the prevention of perinatal transmission of HIV. [20] In this trial, HIV-infected pregnant women were given oral ZDV, a nucleoside reverse-transcriptase inhibitor, from the 14-34 weeks' gestation till the onset of labor (median duration of treatment was 11 weeks). In addition, all received intravenous ZDV during labor. Their newborns were given oral ZDV for 6 weeks. Of interest, most women who participated in this trial had asymptomatic or mildly symptomatic HIV disease. The final results showed that the transmission rate for infants in the placebo group was 22.6%, compared with 7.6% for those in the ZDV group, a 66% reduction in transmission. [4] The efficacy of ZDV prophylaxis in pregnant women with more advanced HIV disease and low CD4+ lymphocyte counts were evaluated in the PACTG 185 trial. [21] The objective of this trial was to evaluated the efficacy of the combination of HIV hyperimmune globulin and ZDV versus the combination of immune globulin and ZDV. The ZDV regimen was similar to the PACTG 076 regimen and approximately 25% of women had received ZDV prior to their current pregnancy. The overall transmission rate was only 4.8% and did not differ by whether the women received HIV hyperimmune globulin or immune globulin. The results confirm the efficacy of ZDV and extend this efficacy to women with advanced disease, low CD4+ lymphocyte counts, and prior ZDV therapy.
The results of PACTG 076 study quickly lead to the wide use of ZDV prophylaxis in HIV-infected pregnant women, particularly in developed countries, to prevent perinatal HIV transmission. However, the high cost of the full PACTG 076 regimen and its complexity limited the use of such regimen in the resource-limited countries where such intervention is needed most. A trial evaluating short-course antenatal/intrapartum ZDV prophylaxis among non-breastfeeding HIV-infected pregnant women was subsequently conducted in Thailand. [22] The regimen included administration of ZDV 300 mg twice daily to pregnant women starting at 36 weeks gestation and 300 mg every 3 hours orally during labor until delivery. No ZDV was given to the newborn infants. The transmission rate was reduced by 50% from the rate of 18.9% in the placebo group to 9.4% in the ZDV group.
A second trial in Thailand compared four different prophylactic ZDV regimens: antenatal ZDV starting at 28 weeks gestation plus neonatal ZDV for 6 weeks (long-long regimen); antenatal ZDV starting at 28 weeks gestation plus neonatal ZDV for 3 days (long-short regimen); antenatal ZDV starting at 36 weeks gestation plus neonatal ZDV for 3 days (short-short regimen); and antenatal ZDV starting at 36 weeks gestation plus neonatal ZDV for 6 weeks (short-long regimen). [23] All women received an identical ZDV regimen orally during labor. At an interim analysis, the transmission rate in the short-short regimen was 10.5%, which was significantly higher than the rate in the long-long regimen. At this point, the short-short regimen was stopped. At the end of the study, the transmission rates were 6.5% for the long-long regimen, 4.7% for the long-short regimen, and 8.6% for the short-long regimen. The efficacy of the three regimens was not statistically different. There was a higher rate of in utero transmission, defined by infant's HIV PCR positivity within seven days after birth, with the short antenatal arms compared with the long antenatal arms. This suggests that longer treatment of the infant cannot substitute for longer treatment of the mother.
» Breastfeeding and mother-to-child
HIV transmission
The risk of mother-to-child HIV transmission in predominantly breastfed populations has been estimated to range from 25% to 48%. [24] Recognition that HIV could be transmitted through breastfeeding has precipitated a major public health dilemma particularly in the developing world. Long promoted as a mean of preventing malnutrition and decreasing infant morbidity and mortality, especially in resource-poor areas, breastfeeding now poses a significant risk of HIV transmission and is responsible for most of postpartum HIV transmission from mothers to infants. Recent studies have helped document the risk of HIV transmission associated with breastfeeding and have suggested that type and duration of breastfeeding are the key factors that affect transmission. Nduati et al conducted a trial in Kenya, in which 425 HIV-infected women were randomly assigned to feed their infants either breast milk or infant formula. [25] The cumulative probability of HIV acquisition among breastfed infants was 37% compared with 21% among the formula-fed infants. Compliance with the feeding protocol was poorer among the women assigned to formula arm; a significant number of infants in this study arm received both breast milk and formula. The effect of type of breastfeeding on HIV transmission was evaluated in South Africa. [26] Mixed feeding, consisting of breast milk and other foods, was associated with highest rates of transmission when compared with exclusive breastfeeding or formula feeding. The study, which requires confirmation, suggests that for women who choose to breastfeed, exclusive breastfeeding may reduce the risk of HIV transmission.
Mbori-Ngacha et al reported the morbidity and mortality among formula-fed and breastfed infants of HIV-infected women in Nairobi, Kenya. [27] In this trial, both study groups had similar mortality rates and incidences of diarrhea and pneumonia during the first 2 years of life. The study also showed an increased incidence of diarrhea and dehydration in the formula arm during the first 3 months of life, a finding that under­scores the protection by breast milk against diarrheal disease in the first 3 months of life. Infants in the breast­feeding arm had better nutritional status, particularly during the first 6 months of life. However, HIV-free survival (remaining alive and uninfected) at 2 years of age was significantly higher in the formula arm. Thus, the use of formula to prevent HIV transmission can be a viable option in the resource-poor setting, if maternal education, clean water, a supply of formula, and access to health care are available and adequate. These factors must be seriously considered before formula feeding is recom­mended to HIV-infected women. This is particularly important in the countries with limited resources where the infrastructure required to lessen the risks of formula feeding and cultural acceptance of formula feeding are unlikely to exist. If formula feeding is not a suitable option, means of making breastfeeding safer for the infants of HIV-infected women should be sought. Such means include exclusive breastfeeding, wet-nursing by an HIV-seronegative woman or family member, early rapid weaning after 3-6 months of age and avoidance of nursing when there is breast inflammation, which may increase the risk of HIV transmission. [26] , [28] , [29] Implementation of these practices requires significant modification of mixed and prolonged breastfeeding commonly practiced in much of developing world. [30] Specific counseling should be provided to HIV-infected expectant women so that each woman can select the feeding method that maxi­mizes benefits and minimizes risks given her individual situation. [31]
» Clinical trials of antiretroviral prophylaxis in breastfeeding populations
Five randomized clinical efficacy trials have been reported in breastfeeding population and all were conducted in Africa. The RETRO-CI trial in Côte d'Ivoire used a treatment regimen identical to the first Thailand ZDV regimen. [32] The women started oral ZDV 300 mg twice daily at 36 weeks gestation and repeated doses of 300 mg every 3 hours from beginning of labor until delivery. The estimated risks of transmission in infants at 3 months of age in the placebo and ZDV groups were 24.9% and 15.7% respectively. This represents a 37% reduction of transmission. The DITRAME study was carried out in Côte d'Ivoire and Burkina Faso. [33] Women were enrolled between 36 and 38 weeks' gestation to receive either ZDV or placebo. ZDV regimen was similar to the RETRO-CI regimen except there was an additional 7-day course of ZDV given to mothers after delivery. The risks of transmission at 6 months of age were 27.5% in the placebo group and 18% in the ZDV group, a 38% reduction of transmission similar to the RETRO-CI study. Data were pooled from both studies and the efficacy of the short peripartum ZDV regimen at 24 months of age was assessed. [34] The cumulative risks of transmission were 30.2% in the placebo group and 22.5% in the ZDV group, a 26% reduction. Of note, approximately 25% of non-infected children in each study group were still being breastfed or had stopped breastfeeding for less than 2 months at their last date known uninfected and thus remained at risk for HIV acquisition.
The other trial with long-term efficacy results, HIVNET 012, was conducted in Ugandan breastfeeding women. [35] , [36] The regimen consisting of a single 200 mg dose of oral nevirapine, a nonnucleoside reverse-transcriptase inhibitor, given to women at onset of labor and a single 2 mg/kg dose to infants within 72 hours after birth was compared with oral ZDV given to women every 3 hours during labor and to the infants for 7 days. The estimated risks of transmission in infants by age 14-16 weeks were 22.1% in ZDV arm and 13.6% in nevirapine arm. The efficacy of nevirapine to reduce transmission compared with ZDV was 38% up to age 14-16 weeks. [36] Because there was no placebo group in this trial, no conclusions can be drawn regarding the efficacy of nevirapine or of the short ZDV regimen versus no treatment. The simplicity, the efficacy and the low cost of nevirapine regimen now make a large-scale implementation to prevent perinatal transmission of HIV even in the most resource-poor settings possible.
The PETRA trial in Uganda, Tanzania and South Africa comprised four study arms to evaluate the effectiveness of three short regimens of a combination of ZDV plus lamivudine (3TC). [37] HIV-infected mothers were randomized to one of four regimens: A, ZDV 300 mg plus 3TC 150 mg twice daily starting at 36 weeks' gestation, followed by oral intrapartum dosing of ZDV every 3 hours and 3TC every 12 hours and by 7 days' postpartum dosing in mothers and infants; B, as regimen A, but without the antepartum component; C, intrapar­tum ZDV and 3TC only; or D, placebo. The combined HIV transmission and infant mortality rates at 6 weeks of age were 7.0% for group A, 11.6% for group B, 17.5% for group C, and 18.1% for group D. HIV infection rates at 18 months were 15%, 18%, 20% and 22%, respectively. Even though regimens A and B were effective at week 6 after birth, their benefits diminished considerable after 18 months, most likely secondary to HIV acquisition via breastfeeding.
A preliminary report was available for the SAINT study, which assessed the efficacy of nevirapine versus ZDV plus 3TC in South Africa. [38] For the nevirapine arm, mothers received a 200 mg dose of nevirapine at labor and again at 24-48 hours postpartum, and infants received a 6 mg dose of nevirapine at 24-48 hours after birth. For the ZDV plus 3TC arm, mothers during labor received ZDV 600 mg for one dose then 300 mg every 3 hour and 3TC 150 mg every 12 hour followed by 7 days postpartum dosing in mothers and infants. At 8 weeks of age, the transmission rates in infants were 13.3% in the nevirapine arm and 10.2% in the ZDV-3TC arm. This is consistent with the HIVNET 012 and PETRA data and suggests that the short intrapartum and postpartum nevirapine and ZDV-3TC regimens have similar efficacy.
The HIVNET 012, PETRA, and SAINT trials provide good evidence that intrapartum and early postpartum antiretroviral prophylaxis reduce perinatal HIV trans­mission substantially among breastfeeding populations. These interventions target the critical period around labor and delivery when the highest rate of mother-to-child transmission of HIV is known to occur. [2] , [3] Because these regimens included short postpartum therapy to mothers and infants, the relative importance of neonatal and maternal components of prophylaxis cannot be deter­mined. It is possible that the substantial decrease in mater­nal HIV viral load in early breast milk from the postpartum regimens may reduce the risk of transmission during early breastfeeding.
» Other relevant studies of antiretroviral prophylaxis
There have been non-randomized studies that raise relevant points for the prevention of mother-to-child HIV transmission in resource-poor settings. An epidemiologic study in non-breastfeeding population from New York state, USA, demonstrated that the transmission rate in the absence of antiretroviral intervention was 26.6% but was reduced to 10% in women who did not receive antepartum ZDV but received ZDV intravenously during labor and whose infants were given ZDV for 6 weeks. [39] Even when the antepartum and intrapartum components of prophylaxis could not be given, some benefits could be gained by giving ZDV to infants within 48 hours after birth (transmission rate, 9.3%). No benefits were observed if neonatal treatment was initiated on day 3 of life or later. Therefore, antiretroviral prophylaxis should be considered in HIV-infected pregnant women and their infants even if the identification of HIV seropositivity is delayed. The rapid HIV testing should help identify HIV infection in pregnant women, who have no prenatal care or prenatal records, so that antiretroviral prophylaxis can be quickly initiated during this critical period.
The efficacy of a modified ZDV regimen on perinatal HIV transmission in a ZDV donation program in Thailand was evaluated. [40] The regimen was similar to the PACTG 076 regimen, but ZDV was given orally every 3 hours during labor. Despite the fact that this is not a clinical trial, the transmission rate in this observational study was 6%. Of interest, the transmission rate in women who started ZDV before 30 weeks' gestation (5.7%) was not significantly different from that in women who started ZDV at or after 30 weeks' gestation (3.3%). This observation supports the effectiveness of short-course antiretroviral regimens seen in other studies.
The use of combination antiretroviral drugs is increasingly feasible in a dynamic world of changing prices as well as expanding experiences, international resources and commitment to increasing access to quality health services in developing countries. In developed countries where there is no or minimal resource constraint, combination antiretroviral therapy has become the standard of care for HIV-infected persons. It is recommended that HIV-infected pregnant women should be offered such therapy for their own health, if indicated, according to current guidelines. [41] , [42] At least two studies suggest the effectiveness of combination antiretroviral therapy in preventing mother-to-child HIV transmission. In a non-randomized trial in a non-breastfeeding population in France, 445 HIV-infected women received 3TC in addition to the standard PACTG 076 ZDV regimen. [43] 3TC was added at 32 weeks gestation through delivery; 3TC was also given to the infant for 6 weeks in addition ZDV. The transmission rate was 1.6%, which was 5-fold lower than the historical control group of women receiving only ZDV. A prospective study in USA and Puerto Rico showed the HIV transmission rates of 10.4% in women receiving ZDV monotherapy, 3.8% in those receiving dual antiretroviral therapy, and only 1.2% in those receiving combination therapy with protease inhibitors. [44] The protective effect increased with the complexity of the regimen, and highly active combination therapy was associated with the lowest rate of perinatal transmission.
» Safety of antiretroviral therapy in pregnancy
Nucleoside Reverse-transcriptase Inhibitors
The examples of antiretroviral drugs in this group are ZDV, stavudine, didanosine and 3TC. They are generally well tolerated and cross the placenta. Teratogenic effects have not been shown in animals in concentrations similar to those achieved in humans. Nucleoside reverse-transcriptase inhibitors bind to mitochondrial DNA polymerase gamma and can cause mitochondrial dysfunction, which may manifest as myopathy, cardiomyopathy, neuropathy, lactic acidosis, fatty liver or hepatic failure. [45] Toxic effects of long-term use of nucleoside reverse-transcriptase inhibitors may be increased in pregnant women. Three cases of fatal lactic acidosis were reported in women who were either pregnant or postpartum and whose antiretroviral therapy during pregnancy included stavudine and didanosine in combination with other antiretroviral agents. [46] Although hepatic failure and lactic acidosis have been reported most commonly with long-term use of stavudine and didanosine, the potential exists with all nucleoside reverse-transcriptase inhibitors. Physicians and pregnant women should be aware of the nonspecific clinical presentations of liver dysfunction and lactic acidosis. Mitochondrial dysfunction may develop in infants who are exposed to nucleoside reverse-transcriptase inhibitors. Possible mitochondrial dysfunction with fatal outcome were reported in a large cohort of infants exposed to ZDV or ZDV-3TC in utero and during neonatal period. [43] , [47] In a review of more than 16,000 children exposed to antiretroviral drugs in USA, no increase in death rates was found among children exposed to nucleoside reverse-transcriptase inhibitors when compared with children with no such exposure. [48] No deaths were found to be definitely related to mitochondrial dysfunction. Monitoring for such toxicity remains ongoing. The rates of symptoms potentially related to mitochondrial dysfunction in the PETRA trial, which included a placebo group and 3 ZDV-3TC groups, were not different among the study groups. [49] Thus, the potential risk of antire­troviral drug-induced mitochondrial dysfunction in an infant appears to be very small and should be compared against the clear benefit of antiretroviral prophylaxis in reducing perinatal transmission of a yet-fatal HIV infection.
Carcinogenesis is another issue of concern related to exposure in utero to nucleoside reverse-transcriptase inhibitors. An increase in the incidence of tumors was observed in rodents exposed in utero to ZDV at 30 times the dose used in humans. [50] However, no increase in the incidence of tumors was found in a similar study using lower doses. [51] The data from PACTG 076 and the Women and Infants Transmission Study demonstrated no tumors of any nature among ZDV-exposed, HIV-uninfected children during the follow-up period of up to 6 years. [52]
Nonnucleoside Reverse-Transcriptase Inhibitors
Both nevirapine and efavirenz readily cross the placenta in primates. Use of efavirenz in early pregnancy is not recommended because of birth defects, including anencephaly and anophthalmia, observed in cynomolgus monkeys after exposure in utero. [42] The common toxic effect of nonnucleoside reverse-transcriptase inhibitors is rash and severe reactions with fatal outcome. In HIVNET 012 trial in which nevirapine versus ZDV was used, the rates of serious adverse events and clinical and laboratory abnormalities were similar between the two study groups. [35]
Protease Inhibitors
There appears to be minimal transplacental passage of protease inhibitors in humans. [42] Pre-clinical reproductive toxicity studies, carcinogenicity and mutagenicity studies have been reviewed extensively. According to the US Food and Drug Administration (FDA) classification, indinavir, amprenavir, and lopinavir/ritonavir are in FDA pregnancy category C. Nelfinavir, ritonavir, and saquinavir are in category B. Category C means that safety in human pregnancy has not been determined and animal studies are either positive for fetal risk or have not been conducted, whereas Category B means that animal studies fail to demonstrate a risk to fetus and well-controlled studies in pregnant women have not been conducted. The toxicity of protease inhibitors among pregnant women appears to be similar to that among non-pregnant women. Hyperglycemia, new-onset diabetes mellitus, exacerbation of existing diabetes, and lipodystrophy have been reported among patients taking protease inhibitors. Pregnancy is itself a risk factor for hyperglycemia; it is unknown if protease inhibitors will increase the risk for pregnancy-associated hyperglycemia. An appropriate diagnostic and monitoring approach to hyperglycemia is essential when the use of protease inhibitors is planned during pregnancy.
Antiretroviral Drugs and Pregnancy Outcome
The combined data of 3920 mother-child pairs from the European Collaborative Study and the Swiss Mother + Child HIV Cohort Study were evaluated for the relationship between type and timing of initiation of antiretroviral therapy and the outcome of pregnancy. [53] Exposure to ZDV monotherapy was not associated with prematurity, but severe immunosuppression and illicit drug use were. Combination antiretroviral therapy was associated with an increased risk for prematurity, with the multivariate odds ratios of 2.6 and 1.8 for infants exposed to combination therapy with and without protease inhibitors, respectively, compared to no therapy. In contrast, in a large cohort of HIV-infected US women who received antiretroviral therapy during pregnancy, the risk of prematurity or low birth weight was not associated with the use of either monotherapy or combination therapy (with or without protease inhibitors). [54] The reason for the differences between the two studies is unclear. It is possible that there are other factors not identified in the studies, such as the status of maternal disease or HIV RNA load, that could explain the differences. These findings however highlight the need for health care providers to discuss risk/benefit and therapy options with HIV-infected pregnant women.
» Viral resistance and mother-to-child HIV transmission
Viral resistance to antiretroviral drugs has become a concern particularly with the increasing global use of antiretroviral therapy to prevent perinatal HIV transmission. The prevalence of resistance mutations in pregnant women varies. The resistance to ZDV in women and infants after ZDV prophylaxis was rare in the PACTG 076 study and the detection of resistance mutations was not associated with an increased risk of perinatal transmission. [55] , [56] In contrast, a ZDV resistance mutation developed in 25% of 142 women in the Women and Infants Transmission Study and the viral mutation was independently associated with increased perinatal transmission. [57] Of interest, this study was before 1994 when ZDV was used for prevention of perinatal transmission. The women in this study were receiving ZDV during pregnancy for their own health, usually without the administration of intrapartum and neonatal ZDV, and they had more advanced HIV disease. Furthermore, almost one-third had been treated with ZDV before pregnancy. These factors could explain the high incidence of viral resistance and increased perinatal transmission.
In the Phase I/II study of nevirapine in HIV-infected pregnant women and infants in Uganda (HIVNET 006), 21 women received a single 200 mg dose of nevirapine at the onset of labor, the same regimen given in HIVNET 012. [58] Plasma HIV reverse transcriptase sequences were analyzed from 15 women at 6 weeks after delivery. Nevirapine resistance mutation (K103N) was detected in three (20%) out of 15 women. Plasma samples before nevirapine was given were available from two of the three women; both samples yielded no nevirapine resistance mutations. Nevirapine resistance mutations was subsequently evaluated in the larger population in HIVNET 012 trial. [59] The mutations were detected in 21 (19%) of 111 women tested at 6-8 weeks after delivery, and the most common mutation found was K103N. The mutations however were not subsequently detected by 12-24 months after delivery. This suggests that the single-dose nevirapine regimen would remain effective in subsequent pregnancies. Nevertheless, implications concerning the transient development of nevirapine resistance from single-dose nevirapine for future treatment of the mothers are unclear. Nevirapine resistance mutations were also observed in 11 (46%) of 24 HIV-infected infants, with Y181C as the most common mutation. The mutation difference in women and infants implies that nevirapine-resistant HIV is selected independently in infants after nevirapine exposure. Similar to the women, the mutations faded from detection in infants over time. This is most likely due to the reduced fitness of nevirapine resistant strains and the replacement by wild-type strain in the absence of the drug. The potential for selection of nevirapine-resistant HIV in women and infants receiving nevirapine prophylaxis must be weighed against the clear benefits of this simple, practical and effective regimen in preventing perinatal HIV transmission.
» Mode of Delivery and Mother-to-Child HIV Trans­mi­ssion
Since perinatal HIV transmission occurs mostly during the peripartum period when fetal exposure to maternal body fluid is most likely, efforts have been focused to interrupt transmission during the peripartum period. Early studies suggested that cesarean delivery before labor began or before the membranes ruptured (elective cesarean delivery) was effective in reducing the rate of transmission. [60] , [61] Subsequently, two large studies have confirmed that perinatal HIV transmission can be reduced by cesarean delivery. In the European Mode of Delivery Collaboration, HIV-infected pregnant women were randomly assigned to elective cesarean section at 38 weeks of pregnancy or to vaginal delivery. [62] Seven (3.5%) of 203 infants who were actually born by cesarean section were infected, compared with 17 (10.2%) of 167 born by vaginal delivery. Within the cesarean section group, four (2.4%) of 169 infants born by elective cesarean section were infected, compared with 3 (8.8%) of 34 born by emergency cesarean section (after labor began or after the membranes ruptured). The transmission rate was lower, though not significantly, in the infants in the cesarean section group (2.1%) than in the vaginal delivery group (3.3%) of women who received ZDV during pregnancy. Since intrauterine transmission cannot be prevented by cesarean delivery and ZDV cannot completely prevent intrauterine transmission, a small number of infants will still be infected despite all the efforts. Intrauterine transmission however is rare. Of interest, the trans­mission rate was lower in infants born by vaginal delivery whose mothers received ZDV (3.3%) than in infants born by cesarean section whose mothers did not receive ZDV during pregnancy (6.8%).
In the meta-analysis of 15 prospective cohorts of more than 7,800 mother-infant pairs, the transmission rate among women undergoing elective cesarean section (8.2%) was significantly lower than that among women having either non-elective cesarean section or vaginal delivery (16.7%). [63] The rates of HIV transmission were 19% with other modes of delivery but without antire­troviral prophylaxis; 10.4% with elective cesarean section but without antiretroviral prophylaxis; 7.3% with other modes of delivery and antiretroviral prophylaxis during prenatal, intrapartum, and neonatal periods; and 2% with both cesarean section and antiretroviral prophylaxis during all three periods. Interestingly, both studies were prior to the use of highly active antiretroviral therapy and the measurement of maternal HIV RNA levels in pregnancy. The use of potent antiretroviral combination, which could significantly reduce the risk for transmission, may diminish the potential impact of elective cesarean delivery upon perinatal HIV transmission.
A cesarean section delivery can have potential adverse effects for the mothers. Several studies reported slightly greater risk of complications among HIV-infected versus uninfected women undergoing cesarean delivery, usually on an urgent rather than elective basis. Complication rates were inversely related to immunologic status and clinical stage of HIV disease. [64] In a large cohort of HIV-infected women, one or more serious complications occurred in 12% of emergency cesarean deliveries, in 6.4% of elective cesarean deliveries, and in 4% of vaginal deliveries. The adjusted relative risk of any postpartum complication was increased by 1.85 after elective cesarean delivery and 4.17 after emergency cesarean delivery, compared with vaginal delivery. [65] Thus it appears that cesarean delivery carried out electively before labor and with intact membranes have a low risk of complications, whereas cesarean procedures performed on an emergent basis have a higher risk of complications. Women with more advanced HIV disease carry a higher risk of complications. In developing countries, the risk-benefit ratio and the cost-effectiveness of cesarean section are different. The post-operative complications are more likely to occur, so the routine use of cesarean section to prevent perinatal HIV transmission may not be of overall benefit.
The use of antiseptic vaginal and cervical washes has been suggested as an inexpensive way to reduce potential viral exposure to infants during delivery. In a trial in Malawi, vaginal disinfection with chlorhexidine 0.25% solution did not reduce perinatal HIV transmission. [66] Results from a study in Kenya using different concen­trations (0.2-0.4%) of chlorhexidine also yielded a similar outcome. [67] However, vaginal disinfection before the membranes are ruptured was associated with a reduction of transmission, especially with higher concentrations of chlorhexidine. The trial in west Africa evaluated the efficacy of daily vaginal suppository with benzalkonium chloride during the last month of pregnancy and labor plus bathing of the infants. The results did not demonstrate any benefit of benzalkonium chloride disinfection on mother to child HIV transmission or perinatal and infant mortality. [68]
» Public Health Perspectives on Prevention of Mother-to-Child HIV Transmission
The prevention of mother-to-child HIV transmission should be incorporated in maternal and child health services. An optimal and country-specific strategy of HIV-specific interventions and strengthening of maternal and child health care needs to be defined. Implemen­tation of such strategy will require a renewed commit­ment to increasing access to quality health services. Any specific intervention package to reduce mother-to-child transmission of HIV should be fully integrated in the overall antenatal, obstetrical, and pediatric care, with the primary goal of reducing overall maternal and infant morbidity and mortality. Such a package should include maternal sexually transmitted disease screening and treatment, routine immunization, iron supplementation, appropriate nutritional education, basic obstetric care, information on HIV prevention and care, voluntary HIV counseling and testing, partner counseling, appropriate infant feeding and family planning options. Serious consideration should be given to routine provision of vitamin A supplementation and vaginal disinfection, considering their potential benefit for maternal and infant morbidity and mortality. Appropriate antiretroviral prophylaxis should be discussed and, whenever possible, should be provided. Infant feeding options should be thoroughly communicated with pregnant women. If women opt for breastfeeding, exclusive breastfeeding should be strongly supported. Those who decide not to breastfeed their children must be ensured access to sufficient quantities of nutritionally adequate breast milk substitutes they can prepare safely. Continuous care of women and their infants should be addressed with specific emphasis on the prevention against opportunistic infections, antiretroviral therapy, and determination of infant's HIV infection status.
A comprehensive approach to reduce mother-to-child HIV transmission offers an opportunity to boost basic health infrastructures and maternal child health services. The public health imperative is clear: large-scale efforts can prevent hundreds of thousands of pediatric HIV infection, provide hope for millions of HIV-affected families and reverse the recent precipitous declines in child survival in the developing world.
» References
1.
UNAIDS. AIDS epidemic update: December 2002. Available at: http://www.unaids.org/worldaidsday/2002/press/update/epiupdate2002_en.doc
2.
Rouzioux C, Costagliola D, Burgard M et al. Estimated timing of mother-to-child human immunodeficiency virus type 1 transmission by use of a Markov model: the HIV Infection in Newborns French Collaborative Study Group. Am J Epidemiol 1995; 142 : 1330-1337.
3.
Bertolli J, St Louis ME, Simonds RJ et al. Estimating the timing of mother-to-child transmission of human immunodeficiency virus in a breast-feeding population in Kinshasa, Zaire. J Infect Dis 1996; 174 : 722-726.
4.
Sperling RS, Shapiro DE, Coombs RW et al. Maternal viral load, zidovudine treatment and the risk of transmission of human immunodeficiency virus type 1 from mother to infant. N Engl J Med 1996; 335 : 1621-1629.
5.
Dickover RE, Garratty EM, Herman SA et al. Identification of levels of maternal HIV-1 RNA associated with risk of perinatal transmission: effect of maternal zidovudine treatment on viral load. JAMA 1996; 275 : 599-605. [ PUBMED ]
6.
Mofenson LM, Lambert JS, Stiehm ER et al. Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated with zidovudine. N Engl J Med 1999; 341 : 385-393.
7.
Garcia PM, Kalish LA, Pitt J et al. Maternal levels of plasma human immunodeficiency virus type 1 RNA and the risk of perinatal transmission. N Engl J Med 1999; 341 : 394-402. [ PUBMED ] [ FULLTEXT ]
8.
The European collaborative Study. Maternal viral load and vertical transmission of HIV-1: an important factor but not the only one. AIDS 1999; 13 : 1377-1385.
9.
John GC, Nduati RW, Mbori-Ngacha DA et al. Correlates of mother-to-child human immunodeficiency virus type 1 (HIV-1) transmission: association with maternal plasma HIV-1 RNA load, genital HIV-1 DNA shedding, and breast infections. J Infect Dis 2001; 183 : 206-212. [ PUBMED ] [ FULLTEXT ]
10.
Chuachoowong R, Shaffer N, Siriwasin W et al. Short-course antenatal zidovudine reduces both cervicovaginal human immunodeficiency virus type 1 RNA levels and risk for perinatal transmission. J Infect Dis 2000; 181 : 99-106. [ PUBMED ] [ FULLTEXT ]
11.
Mandelbrot L, LeChenadec J, Berribi A et al. Perinatal HIV-1 transmission: interaction between zidovudine prophylaxis and mode of delivery in French Perinatal Cohort. JAMA 1998; 280 : 55-60.
12.
Minkoff H, Burns DN, Landesman S et al. The relationship of the duration of ruptured membranes to vertical transmission of human immunodeficiency virus. Am J Obstet Gynecol 1995; 173 : 585-589.
13.
Goedert JJ, Duliege AM, Amos CI et al. High risk of HIV-1 infection for first-born twins. Lancet 1991; 338 : 1471-1475.
14.
Hart CE, Lennox JL, Pratt-Palmore M et al. Correlation of human immunodeficiency virus type 1 RNA levels in blood and the female genital tract. J Infect Dis 1999; 179 : 871-882.
15.
Rasheed S, Li Z, Xu D, Kovacs A. Presence of cell-free human immunodeficiency virus in cervicovaginal secretions is independent of viral load in the blood of human immunodeficiency virus-infected women. Am J Obstet Gynecol 1996; 175 : 122-129.
16.
Coutsoudis A, Pillay K, Spooner E, Kuhn L, Coovadia HM, for the South African Vitamin A Study Group. Randomized trial testing the effect of vitamin A supplementation on pregnancy outcomes and early mother-to-child HIV-1 transmission in Durban, South Africa. AIDS 1999; 13 : 1517-1524.
17.
Fawzi WW, Msamanga GI, Spiegelman D et al. Randomised trial of effects of vitamin supplements on pregnancy outcomes and T cell counts in HIV-1 infected women in Tanzania. Lancet 1998; 351 : 1477-1482.
18.
Rodriguez EM, Mofenson LM, Chang BH et al. Association of maternal drug use during pregnancy with maternal HIV culture positivity and perinatal transmission. AIDS 1996; 10 : 273-282.
19.
Burns DN, Landesman S, Muenz LR et al. Cigarette smoking, premature rupture of membranes, and vertical transmission of HIV-1 among women with low CD4+ levels. J Acquir Immune Defic Syndr 1994; 7 : 718-726.
20.
Connor EM, Sperling RS, Gelber R et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 1994; 331 : 1173-1180.
21.
Stiehm ER, Lambert JS, Mofenson LM et al. 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. J Infect Dis 1999; 179 : 567-575.
22.
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.
23.
Lallemant M, Jourdain G, Le Coeur S et al. A trial of shortened zidovudine regimens to prevent mother-to-child transmission of human immunodeficiency virus type 1. N Engl J Med 2000; 343 : 982-991.
24.
DeCock K, Fowler MG, Mercier E et al. Prevention of mother-to-child transmission of HIV-1 in resource poor countries: translating research into policy and practice. JAMA 2000; 283 : 1175-1182.
25.
Nduati R, John G, Mbori-Ngacha D et al. Effect of breastfeeding and formula feeding on transmission of HIV-1: a randomized clinical trial. JAMA 2000; 283 : 1167-1174.
26.
Coutsoudis A, Pillay K, Kuhn L et al. Method of feeding and transmission of HIV-1 from mothers to children by 15 months of age. AIDS 2001; 15 : 379-387.
27.
Mbori-Ngacha D, Nduati R, John G et al. Morbidity and mortality in breastfed and formula-fed infants of HIV-1-infected women. JAMA 2001; 286 : 2413-2420.
28.
Miotti PG, Taha TE, Kumwenda NI et al. HIV transmission through breastfeeding: a study in Malawi. JAMA 1999; 282 : 744-7449.
29.
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.
30.
Unite Nations Children's Fund. The State of the World's Children. New York, NY: United Nations Children's Fund; 2003.
31.
World Health Organization Technical Consultation on Behalf of the UNFPA/UNICEF/WHO/UNAIDS Inter-Agency Task Team on Mother-to-Child Transmission of HIV. New data on the prevention of mother-to-child transmission of HIV and their policy implications. Conclusions and recommendations. Geneva, Switzerland: World Health Organization; October, 11-13, 2000. Available at: http://www.who.int/reproductive-health/rtis/MTCT/mtct_consultation_october_2000/index.htm
32.
Wiktor SZ, Ekpini ER, Karon JM et al. Randomized clinical trial of a short course of oral zidovudine to prevent mother-to-child transmission of HIV-1 in Abidjan, Côte d'Ivoire. Lancet 1999; 353 : 781-785.
33.
Dabis F, Msellati P, Meda N et al. 6-month efficacy, tolerance, 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 multicenter trial. Lancet 1999; 353 : 786-792.
34.
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.
35.
Guay LA, 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. [ PUBMED ] [ FULLTEXT ]
36.
Owor M, Deseyve M, Duefield C et al. The one year safety and efficacy data of the HIVNET 012 trial. XIII International Conference on AIDS. Durban, July 2000 [abstract LbOr1].
37.
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 trial. Lancet 2002; 359 : 1178-1186.
38.
Moodley D, for the SAINT Study Team. The SAINT trial: nevirapine versus zidovudine + lamivudine in prevention of peripartum transmission. XIII International Conference on AIDS. Durban, July 2000 [abstract LbOr2].
39.
Wade NA, Birkhead GS, Warren BL et al. Abbreviated regimens of zidovudine prophylaxis and perinatal transmission of the human immunodeficiency virus. N Engl J Med 1998; 339 : 1409-1414.
40.
Thisyakorn U, Khongphatthanayothin M, Sirivichayakul S et al. Thai Red Cross zidovudine donation program to prevent vertical transmission of HIV: the effect of the modified ACTG 076 regimen. AIDS 2000; 14 : 2921-2977.
41.
Newell ML, Rogers M. Pregnancy and HIV infection: a European consensus on management. AIDS (suppl 2) 2002; 16 : S1-S18.
42.
Centers for Disease Control and Prevention. U.S. Public Health Service Task Force Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States. MMWR 2002; 51(RR-18):1-38.
43.
Mandelbrot L, Landreau-Mascaro A, Rekacewicz C et al. Lamivudine-zidovudine combination for prevention of maternal-infant transmission of HIV-1. JAMA 2001; 285 : 2083-2093.
44.
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.
45.
Brinkman K, Ter Hofstede HJM, Burger DM et al. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS 1998; 12 : 1735-1744.
46.
Important drug warning: retyped text of a letter from Bristol-Myers Squibb: January 5, 2001. Food and Drug Administration, 2001. Available at http://www.fda.gov/medwatch/SAFETY/2001/Zerit&Videx_letter.htm
47.
Blanche S, Tardieu M, Rustin P et al. Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet 1999; 354 : 1084-1089.
48.
The Perinatal Safety Review Working Group. Nucleoside exposure in the children of HIV-infected women receiving antiretroviral drugs: absence of clear evidence for mitochondrial disease in children who died before 5 years of age in five United States cohorts. J Acquir Immune Defic Syndr 2000; 25 : 261-268.
49.
Lange J, Stellato R, Brinkman K et al. Review of neurological adverse events in relation to mitochondrial dysfunction in the prevention of mother to child transmission of HIV: PETRA study. Second Conference on Global Strategies for the Prevention of HIV Transmission from Mothers to Infants, September 1999, Montreal, Canada.
50.
Olivero OA, Anderson LM, Diwan BA et al. Transplacental effects of 3'-azido-2',3'-dideoxythymidine (AZT) tumorigenicity in mice and genotoxicity in mice and monkeys. J NatlCancer Inst 1997; 89 : 1602-1608.
51.
Ayers KM, Torrey CE, Reynolds DJ. A transplacental carcinogenicity bioassay in Cd-1 mice with zidovudine. Fundam Appl Toxicol 1997; 38 : 195-198.
52.
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.
53.
The European Collaborative Study and the Swiss Mother+Child HIV Cohort Study. Combination antiretroviral therapy and duration of pregnancy. AIDS 2000; 14 : 2913-2920.
54.
Tuomala RE, Shapiro DE, Mofenson LM et al. Antiretroviral therapy during pregnancy and the risk of an adverse outcome. N Engl J Med 2002; 346 : 1863-1870.
55.
Eastman PS, Shapiro DE, Coombs RW et al. Maternal viral genotypic zidovudine resistance and infrequent failure of zidovudine therapy to prevent perinatal transmission of human immunodeficiency virus type 1 in Pediatric AIDS Clinical Trials Group Protocol 076. J Infect Dis 1998; 177 : 557-564.
56.
Palumbo P, Holland B, Dobbs T, et al. Antiretroviral resistance mutations among pregnant human immunodeficiency virus type 1-infected women and their newborns in the United States: vertical transmission and clades. N Engl J Med 2001; 184 : 1120-1126.
57.
Welles SL, Pitt J, Colgrove R et al. HIV-1 genotypic zidovudine drug resistance and the risk of maternal-infant transmission in the Women and Infants Transmission Study. AIDS 2000; 14 : 263-271.
58.
Jackson JB, Becker-Pergola G, Guay LA et al. Identification of the K103N resistance mutation in Ugandan women receiving nevirapine to prevent HIV-1 vertical transmission. AIDS 2000; 14 : F111-F115.
59.
Eshleman SH, Mracna M, Guay LA et al. Selection and fading of resistance mutations in women and infants receiving nevirapine to prevent HIV-1 vertical transmission (HIVNET 012). AIDS 2001; 15 : 1951-1957.
60.
European Collaborative Study. Caesarean section and risk of vertical transmission of HIV-1 infection. Lancet 1994; 343 : 1464-1467.
61.
Kuhn L, Bobat R, Coutsoudis A et al. Cesarean deliveries and maternal-infant HIV transmission: results from a prospective study in South Africa. J Acquir Immune Defic Syndr Hum Retrovirol 1996; 11 : 478-483.
62.
The European Mode of Delivery Collaboration. Elective caesarean-section versus vaginal delivery in prevention of vertical HIV-1 transmission: a randomised clinical trial. Lancet 1999; 353 : 1035-1039.
63.
The International Perinatal HIV Group. The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1. N Engl J Med 1999; 340 : 977-987.
64.
Grubert TA, Reindell D, Kästner R, Lutz-Friedrich R, Belohradsky BH, Dathe O. Complications after caesarean section in HIV-1-infected women not taking antiretroviral treatment. Lancet 1999; 354 : 1612-1613.
65.
Marcollet A, Goffinet F, Firtion G et al. Differences in postpartum morbidity in women who are infected with the human immunodeficiency virus after elective cesarean delivery, emergency cesarean delivery, or vaginal delivery. Am J Obstet Gynecol 2002; 186 : 784-789.
66.
Biggar JR, Miotti RG, Taha TE et al. Perinatal intervention trial in Africa: effect of a birth canal cleansing intervention to prevent HIV transmission. Lancet 1996; 347 : 1647-1650.
67.
Gaillard P, Mwanyumba F, Verhofstede C et al. Vaginal lavage with chlorhexidine during labour to reduce mother-to-child HIV transmission: clinical trial in Mombasa, Kenya. AIDS 2001; 15 : 389-396.
68.
Mandelbrot L, Msellati P, Meda N et al. 15 Month follow up of African children following vaginal cleansing with benzalkonium chloride of their HIV infected mothers during late pregnancy and delivery. Sex Transm Infect 2002; 78 : 267-270.
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