Marazzi MC, Liotta G, Nielsen-Saines K, et al. Extended antenatal antiretroviral use correlates with improved infant outcomes throughout the first year of life. AIDS. 2010, Nov 27;(24):2819-26.
Use of triple antiretroviral therapy (ART) during pregnancy and continued during breastfeeding has been shown to be the most effective intervention for maternal health for women in need of ART and is efficacious in reducing maternal to child transmission of HIV. In developed countries, transmission has fallen below 2% with use of triple ART.(1, 2) Authors of this study have previously reported on HIV transmission rates of 5% and less among children born to women who received triple ART during pregnancy in Mozambique, Malawi, and Tanzania.(3)
To evaluate the impact of triple ART during pregnancy and extended postpartum on infant outcomes in a cohort of HIV infected mother-infant pairs.
DREAM (Drug Resource Enhancement against AIDS and Malnutrition) centers providing prevention of mother to child transmission (PMTCT) services in Mozambique or Malawi.
Retrospective cohort using pooled data from health clinics in Malawi and Mozambique.
HIV-infected pregnant women and their live-born infants followed in PMTCT programs.
All pregnant women and their live-born infants who were followed at DREAM centers in Mozambique or Malawi from July 2005 to December 2009, had prenatal care at a DREAM site, had available pregnancy outcome data, gave informed consent to participate in the program, expressed intent to follow-up in the program, and who intended to breast-feed were included in the retrospective cohort.
Triple ART was provided to HIV-infected women according to World Health Organization (WHO) guidelines as part of a comprehensive package which also provided nutritional supplementation to those with low body mass index (BMI), AIDS defining conditions, and pregnancy/lactation. ART was initiated at 14 weeks gestation for women who required it for their own health (CD4<350 cells/µl) and continued indefinitely. Triple ART prescribed for PMTCT purposes was initiated at 25 weeks gestational age and was maintained until six month post partum for women who chose to breastfeed. At four to five months post delivery, women on ART for PMTCT were counseled to wean their infants over the next two months, which was supervised by nutritionists. ART was stopped once weaning was completed. Data were collected through electronic medical records, including laboratory data (viral load [HIV-1 RNA PCR], CD4, HIV-1 bDNA PCR, hemoglobin and liver transaminases).
Infant outcomes included HIV infection status measured by HIV-1 bDNA at one, six, and 12 months of age, infant death, HIV-free survival at 12 months of age, growth parameters (weight-for-age Z scores), low birth weight (<2.5 kg) and serious adverse events such as anemia (Hb <8.0g/dl) and hepatic toxicity (five times the upper limit of normal of liver function tests). Pregnancy outcomes included abortion/still births. Maternal outcomes were maternal death and adverse events, including grade three or four liver toxicities, anemia, Steven-Johnson syndrome and grade three or four skin rashes.
Data were censored at the time of death, at the last visit for patients who were lost to follow-up or at December 31, 2009. HIV transmission rates were compared according to length of maternal pre-delivery ART. Logistic regression was performed using a forward stepwise model for outcomes of pediatric HIV infection and infant mortality. A multivariate Cox proportional survival analysis was conducted for evaluation of HIV-free survival by pre-delivery length of ART.
Of the 3,273 pregnant women enrolled, there were 42 maternal deaths (1.2%), 169 abortions/still births (5.2%), and 3,071 pregnancies which came to term with 3,148 live-born infants, including 77 twins. By one month of age, 1.3% of infant were lost to follow-up, 0.8% died and 0.8% were determined to be HIV-infected. Overall, by 12 months of age, 11.5% were lost to follow-up, 6.7% had died, and 2.0% were HIV-infected.
Rates of HIV infection were low at all time points. The highest transmission rate was at one month of age among infants born to women with less than 30 days of ART exposure (1.9%). Rates of HIV infection and rates of HIV infection combined with infant death varied by length of maternal ART prior to delivery. At one month of age, HIV infection and/or infant death was higher among infants born to women with less than 30 days of antenatal ART (3.7%) compared to those with >90 days (1.2%) (p=.013). Transmission and/or death rates at 12 months were twice as high in women with >30 days of triple ART exposure pre-delivery (14%) compared to women who received 90 days of treatment pre-delivery (6.9%). Fifty percent of the episodes of HIV transmission and HIV transmission and death occurred in women with baseline CD4 count >350. Women with CD4 >350 initiated ART at a mean gestational age of 17.2 weeks; those with CD4 <350 initiated ART at mean gestational age of 23 weeks.
When stratified by baseline maternal CD4 counts, HIV infection or infant death by one month of age was less among those who received >30 days of antenatal ART exposure compared to <30 days (Mantel-Haenszel OR 0.42, 95%CI 0.22-0.81). Antenatal ART exposure >30 days was significantly protective against HIV transmission and infant death compared to <30 days among women with baseline CD4 < 350 at one month of age (1.6% vs. 4.3%, OR 0.36, 95%CI 0.15, 0.88), six months of age (3.2% vs. 7.9%, OR 0.39, 95%CI 0.20-0.76) and 12 months of age (3.9% vs. 9.5%, OR 0.39 95%CI 0.20-0.76).
In multivariate analysis, baseline maternal CD4 cell count and maternal BMI were not associated with HIV transmission or combined HIV transmission and/or death. Absence of maternal ART prior to delivery was associated with HIV transmission and/or infant death at all time points with a relative risk of 1.6 (95% CI 1.06-2.38) at one month of age, 1.3 (1.04-1.80) between one to six months of age and 1.5 (1.15-1.99) between six to 12 months of age. Maternal viral load was associated with HIV infection at six to 12 months (RR=3.21, 95%CI 1.27-8.13), and with HIV infection and/or death at one to six months of age (RR=1.44, 1.03-2.01).
Cumulative HIV-1 free survival at 12 months was 92.5% and was greater if mothers received >30 days of triple ART pre-delivery (93.5%) compared to those who received less than 30 days (91%) (p<.001). Overall infant mortality (67/1000) was lower than infant mortality rates in the general population of Mozambique (100/1000) and Malawi (78/1000).(4)
Serious adverse events, including rates of anemia (3.9%) (Hb <8.0g/dl) or hepatic toxicity (0.3%) (five times the upper limit of normal for liver function tests) were low. Moderate to severe growth failure, as defined by weight-for-age z scores (WAZ) of less than -2, were seen in 8.1% of 477 infants measured at one week of age, 6% of 2002 infants measured at 6 months of age, and 22.7% of 2518 infants measured at 12 months of age. Low birth weight was 11.5%. Details of infant growth parameters are reported separately.(5)
Grade three or four liver toxicity likely associated with triple ART exposure was reported in 2.1% of mothers. Incidence of Steven-Johnson Syndrome and grade three or four skin rashes were reported in 1.2% and 2.4% of mothers, respectively. Details on maternal and pregnancy outcomes are reported separately.(6)
Data from this retrospective cohort of over 3,000 mother-infant pairs, demonstrate that triple ART given both antenatal and postpartum for both women in need of treatment and for PMTCT resulted in an overall HIV transmission rate in a breastfeeding population of 2% at 12 months of age and HIV-free infant survival of 92.5%.
Although these data are from a large number of mother-infant pairs, it is not clear how representative these patients who enrolled in the DREAM Clinics are of pregnant HIV-infected women in Mozambique and Malawi, as neither characteristics of the pregnant women (demographics, socio-economic status, clinical status, etc.) nor number and characteristics of the clinics (e.g., urban or rural, size of patient population, etc.) was provided in a Table or text. There was 11.5% loss to follow-up of infants at 12 months of age, with a greater loss to follow-up in the second six months. Among those who were lost to follow-up, a substantial proportion may have died, leading to concerns about accuracy of survival estimates. Although overall infant mortality was lower than that of either country, mortality rates were higher during the second six months of life (3.5%) than either the neonatal period (0.3%) or one to six month period (2.6%), which is the inverse of most country mortality data. Authors attribute this to the weaning and introduction of other foods from six month of age and older which accompanied maternal ART interruption for those who did not need ART for their own health. Moderate-to severe malnutrition increased from 6% of infants at 6 months to 23% by twelve months which, the authors comment, is likely also due to the impact of weaning. Detailed infant growth parameters were reported elsewhere.
This study demonstrates the feasibility and beneficial effects from delivering antenatal and postnatal triple ART to pregnant HIV-infected women on reduction of HIV transmission and improvement in HIV-free survival in low resource settings, consistent with other studies.7 WHO now recommends initiation of ART for all HIV-infected pregnant women for their own health who have CD4 cell counts of ≤350 cells/µl, irrespective of WHO clinical stage, and for all women in WHO clinical stage three or four irrespective of the CD4 cell count.(7, 8) For pregnant women who are not in need of treatment, ARV prophylaxis is recommended to prevent MTCT during pregnancy, delivery and breastfeeding. During breastfeeding, ARV prophylaxis can be provided either to the mother or the infant. This allows for more effective postpartum interventions and emphasizes that PMTCT does not stop at delivery but includes postpartum and breastfeeding follow up and interventions for both the mother and infant. One option is triple ART begun as early as 14 weeks gestation and continued until one week after breastfeeding along with nevirapine (NVP) or zidovudine (AZT) from birth until four to six weeks of age for the infant. The other option is prenatal AZT from as early as 14 weeks gestation, sd-NVP during labor, AZT and lamivudine (3TC) for seven days postpartum and for breastfeeding infants, daily NVP from birth to a minimum of four to six weeks and until one week after all exposure to breast milk has ended.(7) Given that these ARV interventions given to either the mother or HIV-exposed infant can significantly reduce postnatal transmission of HIV through breastfeeding, WHO has also issued revised HIV and infant feeding guidelines that recommend exclusive breastfeeding for first six months of life, introducing appropriate complementary foods thereafter and continued breastfeeding for the first 12 months of life.(9)
- Dorenbaum A, Cunningham CK, Gelber RD, et al. International PACTG 316 Team. Two-dose intrapartum/newborn nevirapine and standard antiretroviral therapy to reduce perinatal HIV transmission: a randomized trial. JAMA 2002 Jul 10;288(2):189-98.
- Centers for Disease Control and Prevention. Achievements in public health: reduction in perinatal transmission of HIV-infection-United States, 1985-20005. MMWR 2006; 55(21);592-597.
- Palombi L, Marazzi MC, VoetbergA, Magid NA. Treatment acceleration program and the experience of the DREAM program in prevention of mother-to-child transmission of HIV. AIDS 2007;21:S65-S71.
- World Health Organization. World Health Statistics 2008. WHO Library Cataloguing-in-Publication Data. ISBN 978 92 4 0682740
- Palombi L, Buonomo E, Scarcella P, et al. Provision of highly active antiretroviral therapy (HAART) to mothers while breastfeeding ad nutritional supplementation during the weaning process favorably impact infant growth and survival in African HIV-exposed infants In: Proceedings of the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention;19-22 July 2009;Cape Town, South Africa. Abstract TUPECO44.
- Marazzi MC, Palombi L, Nielsen-Sainer K, et al. Favorable pregnancy outcomes with reduction of abortion stillbirth, and prematurity rates in a large cohort of HIV+ women in South Africa receiving highly active antiretroviral therapy (HAART) for prevention of mother-child-transmission (PMTCT). In: Proceedings of the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention;19-22 July 2009;Cape Town, South Africa. Abstract TUAC1024.
- World Health Organization. Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants: towards universal access. Recommendations for a public health approach (2010 version)
- World Health Organization. Rapid Advice: use of antiretroviral drugs for treating pregnant women and prevent HIV infection in infants.
- World Health Organization. Guidelines on HIV and infant feeding. 2010. Principles and recommendations for infant feeding in the context of HIV and a summary of evidence.