The study described below is reported in JAMA (Jnl of the American Medical Assn) Apr 25, 2001 (285: 2083-93). A total of 445 HIV-1infected pregnant women were enrolled as the study cohort from February 1997 to September 1998; controls consisted of 899 pregnant women who had received zidovudine monotherapy in May 1994 to February 1997 as standard care.
Reported is a study in France of AZT/3TC for preventing mother-to-child transmission of HIV. The transmission rate was low 1.6% (7/437) and similar with and without elective caesarean (1.10% vs 1.75%). Viral load was reduced 1.24 log. 74% of women had <500 copies/ml at delivery. But, of the 452 newborns, there were "significant hematologic adverse events reported in the children included 81cases of neutropenia and 68 cases of anemia; 9 required blood transfusions and 19 discontinued treatment because of these abnormalities". Several infants developed mitochondrial toxicity, which has been rare, but this has not been reported in the USA. Whether or not the mi tochondrial toxicity was related to the AZT/3TC was questioned. Authors reported two uninfected children died at age 1 year from neurologic complications related to mitochondrial dysfunction. See follow-up outcomes below. Three women who transmitted HIV had plasma HIV-1 RNA levels of less than 500 copies/mL at delivery. This shows that HIV can be transmitted when viral load is under 500 copies/ml. One had an elective cesarean delivery at 38 weeks (case 4), and the others had uneventful vaginal term deliveries. None of these women breastfed.
Sixteen children (4%) had major birth defects, including 4 cardiac malformation cases, 4 cases of polydactyly, 3 talipes cases, and 1 case each of congenital diaphragmatic hernia, hydronephrosis, imperforate anus, genu recurvatum with a suburethral cyst, and hypospadia. One child each had Down syndrome, Ito nevus, and sickle cell anemia. The prevalence of major birth defects was of the order expected in children not exposed to antiretroviral drugs, which ranges from 2% to 5% in most registries and was 2.7% among liveborn children in Paris during a10-year period.
For children in the study group, the mean (SD) duration of follow-up was 16 (4) months. Follow-up data were available after age 6 months for 96% of children and after age 12 months for 89%.
A total of 397 adverse events, 180 biological (ie, involving hematologic or blood chemistry alterations) and 217 clinical in nature, were reported among 238 of the 452 children in the lamivudine-zidovudine cohort. Altogether, 151 hematologic adverse events, defined as moderate to severe according to the age-adjusted ACTG classification,17 occurred during exposure to study drugs. These mostly consisted of neutropenia (81 cases) or anemia (68 cases), leading to blood transfusion because of clinical symptoms in 9 infants (5 had mild symptoms [pallor or tachycardia] and 4 had severe symptoms [cardiac insufficiency or dyspnea]) and to premature treatment discontinuation for 19 children. Of the children with hematologic toxic effects during receipt of lamivudine-zidovudine, none had persistent serious anemia at the last follow-up, and only 1 had persistent moderate neutropenia at age 6 months. Liver abnormalities without proven cause were recorded in 6 children (1 case of severe jaundice and 5 of alanine aminotransferase elevations >2.5 times the ULN); only 1 was persistent (3 times the ULN) at age 18 months. Six children had asymptomatic elevations of serum lipase levels to more than 2.5 times the ULN. One of these children had a persistent lipase elevation (3 times the ULN) after age 1 year and was diagnosed with mitochondrial dysfunction, as previously reported.21
Of the 217 clinical adverse events reported among children, most were due to a known cause unrelated to study drugs (ie, perinatal complications, [53 cases, principally intrapartum asphyxia, withdrawal syndromes, and maternal-fetal bacterialinfections], hospitalization for infectious disease [117 cases], or various other reasons [15 cases]). Sixteen children (4%) had major birth defects, including 4 cardiac malformation cases, 4 cases of polydactyly, 3 talipes cases, and 1 case each of congenital diaphragmatic hernia, hydronephrosis, imperforate anus, genu recurvatum with a suburethral cyst, and hypospadia. One child each had Down syndrome, Ito nevus, and sickle cell anemia. The prevalence of major birth defects was of the order expected in children not exposed to antiretroviral drugs, which ranges from 2% to 5% in most registries and was 2.7% among liveborn children in Paris23 during a 10-year period.
Neurologic signs/symptoms were reported in 12 children who did not have HIV infection and had no other known infectious or genetic disease. Six had febrile seizures without other symptoms. Two children with neurologic complications were diagnosed as having mitochondrial dysfunction and died at age 1 year, as previously discussed.21 No other children died during follow-up. Two children had hydrocephalus, 1 of whom had severe neurodevelopmental delay; 1 had severe behavioral problems and cognitive delay; and 1 had Guillain-Barré syndrome. These 12 children all also were reported as having adverse events involving hematologic or blood chemistry alterations during the first 6 weeks. Another 2 children had unexplained failure to thrive. Follow-up of these children is ongoing. The prevalence of mitochondrial cytopathies in the general population has recently been estimated as being about 60 in 100 000 in a large 7-year study in Finland.
Rate of pregnancy complications did not differ between the 2 cohorts (M.-J. M., unpublished data). Birth characteristics of the children in the study group did not differ significantly from those of the control group with the exceptions noted below. However, the mean (SD) hemoglobin level was significantly lower in the study group than in the control group at birth (15.0 [2.2] g/dL vs 15.5 [2.5] g/dL; P = .004) and at age 1 month (9.8 [1.4] g/dL vs 10.3 [1.6] g/dL; P<.001). The mean (SD) neutrophil count was significantly lower in the study group than in the control group at birth, but not at age 1 month.
"Combination Prophylaxis for Prevention of Maternal-Infant HIV Transmission: Beyond 076"
Nathan Shaffer, MD
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Since 1994, rapid implementation of the landmark ACTG 076 study regimen has led to a dramatic reduction in perinatal HIV (human immunodeficiency virus) transmission in the United States and other developed countries.1 Cohort studies, registries, and surveillance data have all confirmed the effectiveness of the 3-part zidovudine monotherapy regimen, administered orally to the pregnant woman beginning at 14 to 34 weeks' gestation, intravenously during labor, and orally to the newborn for 6 weeks. In the absence of breastfeeding, use of this regimen has resulted in perinatal transmission rates of 4% to 10% in the United States and Europe.2 In conjunction with the 076 regimen, elective caesarean delivery or combination antiretroviral therapy has resulted in transmission rates of less than 2%.2-4 Although the data on combination therapy have been quite limited, there is a growing conviction that perinatal HIV transmission can be reduced to near zero with early identification of the HIV-infected pregnant woman and aggressive clinical management.5
The use of combination antiretroviral therapy for pregnant women has become increasingly common because of the recommendation that HIV treatment for the woman should not be withheld during pregnancy.2 However, these treatment decisions are complex and require consideration of the potential toxicity during pregnancy and 2 separate but related issues: antiretroviral treatment of the woman's HIV infection and antiretroviral chemoprophylaxis to reduce the risk for perinatal transmission. The study reported in this issue of THE JOURNAL by Mandelbrot et al6 provides a systematic evaluation of the efficacy and toxicity of combination prophylaxis during pregnancy. The study evaluates the addition of lamivudine to the standard 076 zidovudine regimen, with lamivudine administration beginning at 32 weeks' gestation in the mother and lamivudine administration to the newborn for 6 weeks. The study design is a historical comparison with a previous national cohort of HIV-infected pregnant women who had received the 076 regimen. A randomized trial was not conducted because of the belief among participating clinicians that the combination therapy would be superior to zidovudine monotherapy. Although the authors acknowledge the potential limitations of their study design, particularly with regard to possible temporal changes in transmission risk or clinical management, their findings are based on a large, carefully followed cohort with baseline characteristics and risk similar to those of the earlier cohort.
The efficacy findings for the lamivudine-zidovudine combination are impressive. Of 437 HIV-exposed children with known infection status, only 7 (1.6%) were infected with HIV perinatally. Rates were similarly low among those with and without elective caesarean deliveries (1.10% vs 1.75%, respectively). The results of a multivariable analysis controlling for mode of delivery, history of antiretroviral therapy, and measures of maternal HIV disease progression (including viral load) showed that the rate of perinatal HIV transmission was 5-fold lower than in the earlier zidovudine comparison group (6.8%).
In contrast to the 076 study, in which viral load was reduced only 0.24 log and accounted for little of zidovudine's efficacy in the 3-part regimen,7 the lamivudine-zidovudine combination resulted in a median paired decrease in viral load levels of 1.24 log. The proportion of women with viral load levels of less than 500 copies/mL increased from 23% at enrollment to 74% at delivery. Although it is likely that the regimen offers protection via several mechanisms, including prophylaxis in the fetal circulation and post-exposure prophylaxis in the newborn, the findings of sharply reduced and low viral load levels provide important new evidence that combination therapy can reduce viral load at the time of delivery and can add significant additional protection to that afforded by the 076 regimen alone.
The safety and toxicity data emphasize the need for close monitoring during th e administration of the combination therapy, particularly for hematologic and hepatic toxicity. A main concern appears to be increased risk of hematologic toxicity in the infants (nearly all of whom will be uninfected). There were a total of 452 infants born to 445 women in the lamivudine-zidovudine study group. Significant hematologic adverse events reported in the children included 81cases of neutropenia and 68 cases of anemia; 9 required blood transfusions and 19 discontinued treatment because of these abnormalities. To the extent that ascertainment was complete, these data may represent a minimum estimate of the number of substantial hematologic events that can occur in children receiving this combination therapy. In addition, several infants developed mitochondrial dysfunction, which has been reported as a rare, late complication of both zidovudine and lamivudine exposure in France, but which has not been seen in the United States.8, 9 Although the frequency of serious adverse events seems increased, the frequency of toxicity observed for combination therapy was similar to that observed in the comparison zidovudine cohort.
These data will be extremely useful to the Public Health Service Task Force and other consensus bodies charged with making recommendations regarding new perinatal regimens. One question that future research initiatives should address is whether, in addition to the 076 regimen, administration of lamivudine to only the mother late in pregnancy could achieve similarly low transmission rates with less toxicity to the infants. Concerns about long-term effects, which are still not known for zidovudine, underscore the importance of recommendations for long-term follow up of any child with in utero exposure to antiretroviral drugs and emphasize the value of exposure registries such as the Antiretroviral Pregnancy Registry.2, 10 A second important concern highlighted in this study is the rapid development of resistance to lamivudine (characterized by detection of the M184 variant). However, although it was estimated that about one third of the women included in a genotyping study developed resistance, much of this resistance may have been related to ongoing lamivudine treatment in the mother postpartum. Among women with evaluable data, for the 12 women who received lamivudine for less than 1 month (it was likely that therapy was stopped after delivery), the mutation was not detected; for those receiving lamivudine for 1 to 2 months, it was identified in 14 of 70 (20%) women, compared with 37 of 74 (50%) women who received lamivudine for more than 2 months. In addition to monitoring for resistance, further research is needed to determine the clinical significance of the M184V mutation, including whether the virus with the mutation is more transmissible than the wild-type virus. The data in this study suggest that perinatal transmission may be associated with the mutation, although this finding did not reach statistical significance. Furthermore, it is not known whether this mutation will persist in the absence of ongoing treatment, whether it would affect the response to later initiation of highly active antiretroviral therapy for the woman, or whether it would affect the efficacy of a combination regimen if used in a subsequent pregnancy.
The findings of Mandelbrot et al may also have implications for developing countries focusing on the use of short-course antiretroviral regimens initiated in late third trimester. The Perinatal Transmission (PETRA) study, involving a predominantly breastfeeding population in Africa, used a similar lamivudine-zidovudine combination but provided treatment for only 4 weeks to the mother and 1 week to the infant in its long-treatment group.11 The efficacy level in this group was estimated at 50% and transmission rate was 8%. Comparison of viral load data from the PETRA study (if available) with the viral load data in the current study may explain some of the differences in early transmission rates and suggest an optimal duration of antenatal therapy with lamivudine. For countries that are implementing the short-course zidovudine regimen evaluated in Thailand,12 addition of antenatal lamivudine, with or without neonatal lamivudine, may provide additional significant protection by further reducing viral load level and raises the possibility of achieving transmission rates of less than 5% with abbreviated regimens. The potential additional benefit of lamivudine vs nevirapine in resource-poor settings also will be important to evaluate.
Until recently, the emphasis in adult treatment of HIV infection was on initiating combination antiretroviral therapy as early as possible,13 which likely led some clinicians and patients to decide to initiate or continue combination therapy early in pregnancy. However, in February 2001, the adult treatment guidelines were revised substantially.13 The new guidelines are more conservative: initiation of treatment is recommended in asymptomatic individuals with fewer than 350 CD4 cells/µL or with plasma RNA levels greater than 55 000 copies/mL. Although it is too early to assess the impact of these new recommendations on treatment decisions for pregnant women, it is likely that the new adult treatment recommendations will result in fewer pregnant women starting treatment for their own HIV infection during pregnancy. Thus, the issue of combination therapy as prophylaxis against perinatal transmission will become increasingly important. In this regard, the study by Mandelbrot et alprovides important and timely data on the efficacy and safety of the lamivudine-zidovudine combination.
In developed countries, additional interventions that enhance the 076 regimen, such as combination lamivudine-zidovudine and zidovudine plus caesarean delivery, offer the possibility of virtually eliminating perinatal HIV transmission. Barriers to this goal include identifying and offering prophylaxis to all HIV-positive pregnant women inantenatal care, and providing effective interventions for HIV-infected women who present in labor. In sharp contrast, in resource-poor countries where the problem is so much greater, the urgent challenge is to implement basic perinatal HIV prevention programs offering proven, simplified interventions.