Introduction

JNNFI

Journal of Neonatology

0973-21870973-2179

National Neonatology Forum

jn-18-4-002

Symposium on Neonatal HIV

Trends In The Prevention Of Neonatal HIV

Holla

¹Nair

MNG

¹Neonatologist, Dept of Pediatrics, Army Hospital (Research & Referral), Delhi Cantt.²Consultant and Head, Dept of Pediatrics, Army Hospital (Research & Referral), Delhi Cantt.

2004

184511

Introduction

The human immunodeficiency virus (HIV) is transmitted through sexual contact and exposure to infected blood or blood components and perinatally from mother to neonate. An unfortunate outcome of the adult HIV/AIDS epidemic is the transmission of HIV from mother to child. Worldwide, one in ten of those who become newly infected with HIV are children under age 15. During 2003, half a million children died due to AIDS¹. The vast majority of these children contract HIV through their mothers due to perinatal transmission, which accounts for approximately 3.35% of overall transmission of HIV in India².

Clearly, the best way to prevent transmission of the virus from the mother to the fetus/ infant is to prevent the initial transmission of HIV/AIDS to the mother. For women already infected with HIV, steps can be taken to reduce the likelihood of HIV transmission from mother to infant.

Perinatal transmission occurs during the antenatal, intrapartum and during the postnatal periods. In the absence of any intervention, rates of MTCT of HIV can vary from 15% to 30% without breastfeeding, and can reach as high as 30% to 45% with prolonged breastfeeding³.

Magnitude of the problem

Since the first evidence of HIV infection documented in Chennai, 68,908 cases of AIDS have been reported in India. The national adult prevalence rate of HIV is 0.8% with an estimated 0.7-2.4 million HIV positive women in the age group 15-49 years⁴. In a study conducted by NACO in 2000-2001 in 5 high prevalence states (Maharashtra, Tamil Nadu, Karnataka, Andhra Pradesh and Manipur) the antenatal prevalence was 1.7% ⁵.

Clinical trials in a number of countries have demonstrated that MTCT can be greatly reduced through a short course of antiretroviral therapy (ART).

As a result of these trials, ART is now recommended as part of the standard package of care for HIV-positive women and their potentially infected infants. In June 2001 the United Nations Special Assembly on HIV/AIDS set reduction targets of 20% and 50% for the numbers of children newly infected with HIV by 2005 and 2010 respectively⁶.

Timing of transmission

Early transmission (in utero) is defined as that which may be detected within the first 48 hours of life. Late transmission (intrapartum) is defined as negative virologic evaluations during the first week, with evidence of HIV detection between 7 and 90 days of age in the absence of breastfeeding.

Voluntary HIV counseling and testing

The issue of voluntary vs. mandatory HIV testing during the antenatal period has been a subject of debate. The advantages of ascertaining a pregnant woman's HIV status before delivery are clear: transmission to the baby can be roughly halved by avoiding breast feeding and reduced by a further two thirds by the administration of retroviral therapy. Both ‘high risk’ and anonymous testing have been found to be unsatisfactory^7,8. In India, pre-test counseling is not universally available. An additional ramification of antenatal testing which is not often paid adequate attention is the testing of those women who have abortions.

Antiretroviral therapy

In 1994 there was a major breakthrough in the prevention of vertical acquisition of HIV. It was demonstrated that zidovudine monotherapy, given during the second and third trimester of pregnancy, administered intravenously during delivery, and given to infants for six weeks, reduced the risk in a non-breastfeeding population by two-thirds⁹. When combined with elective caesarean section this regimen resulted in a transmission rate of 2% or less, in non-breastfeeding populations.

Antiretroviral drugs decrease viral replication (and therefore viral load) during pregnancy and delivery and through chemoprophylaxis to the exposed neonate, decrease transmission. Various chemoprophylactic regimes used in randomized, controlled trials include zidovudine, lamivudine (3TC), nevirapine either singly or in various combinations (table ). Most of the regimes have included an antenatal, an intrapartum and a neonatal component.

Women who are identified as being infected in the antenatal period, and who have clinical indications to be treated with ART combinations for their own disease, should be given the appropriate treatment based the stage of the disease with a triple combination of ZDV+3TC+NVP or d4T+3TC+NVP. Efivarenz should be avoided due to its teratogenic potential¹⁰.

The increasing use of complex and potent ART combinations in pregnancy in some settings, particularly during the first trimester, has raised questions relating to pregnancy outcome. In an analysis of European data on nearly 4000 mother-child pairs, use of antenatal combination therapy with a protease inhibitor (PI) was associated with a two and a half time increased risk of premature delivery compared with no treatment¹¹. Clinical trials (PACTG 076 and 185) and observational data have shown no evidence of an increased risk of congenital malformations associated with exposure to ZDV prophylaxis¹². Lower neonatal hemoglobin levels related to antenatal ZDV prophylaxis, which normalized by 12 weeks of age have been reported by Connor et al⁹. Lactic acidosis is a well-known toxicity related to nucleoside analogue drugs, possibly associated with mitochondrial toxicity. However, fetal or neonatal side effects have not been studied in detail. The most frequent adverse effects of NVP are hepatotoxicity and cutaneous rash. However, if well tolerated, NVP is one of the drugs recommended during pregnancy. No evidence of 3TC intolerance or toxicity during pregnancy has been reported.

A recent trial has evaluated the role of administering a single drug (NVP) versus dual drug (ZDV + NVP) to the neonate as a post exposure maneuver to prevent MTCT in mothers who had not received antenatal or peripartum prophylaxis¹³.

Emergence of viral resistance is frequent during ARV treatment especially when the treatment involves the use of only one or two drugs. Such resistance may interfere with future treatment options but there is lack of data to quantify this risk. Resistance to NVP develops rapidly, and in the HIVNET 012 trial 20% of NVP-exposed women had evidence of NVP resistance at 6 week post-partum, as did 46% of the infants who became infected¹⁴. In the PACTG 316 trial, the incidence of resistance rose from 2.3% to 15%, with the use of nevirapine in the antenatal period and the development of resistance had no correlation with CD4 count or HIV RNA viral load¹⁵.

Intrapartum transmission is related to cervicovaginal HIV viral load. The effect of zidovudine on plasma and genital human immunodeficiency virus type 1 in HIV positive women who had not received ART was found to decrease by 1.1 log₁₀ after 7 days¹⁶. This short-term effect of zidovudine on plasma and genital HIV-1 is important for improving perinatal HIV-1 interventions.

Breast feeding

The prophylactic ARV drug regimens with one or more drugs have been shown to prevent 50-80% infections that occur in the peripartum period as assessed at 6-8 weeks of age. However, the impact on overall MTCT rates is less due to the continued transmission risk in the post-natal period during breastfeeding. Women with clinical indications for ARV treatment and who are breastfeeding should continue their ARV therapeutic regimen to delay disease progression.

It is estimated that breastfeeding increases the overall risk of MTCT by 14% for women with established HIV infection and by 29% for women who become infected during lactation¹⁷. While the factors affecting transmission risk are poorly understood, HIV-specific cytotoxic T-lymphocyte (CTL) responses play a critical role in controlling HIV levels in blood. A possible role for limiting transmission through breast milk has been ascribed to CD8⁺ cytotoxic T cells in the breast milk¹⁸. Level of HIV RNA in breast milk is also an important determinant of transmission. In a study in Malawi, Semba et al found the breast milk viral load to vary from <200 to 42,627 copies/ml¹⁹. A positive correlation with breast milk sodium, mastitis and transmission was found.

Various factors may play a role in a mother deciding to breast feed. Inability to afford formula, fear of social repercussions of not breast feeding, and advice by the counselor have been cited²⁰. The importance of exclusive breast feeding must be emphasized to every HIV positive mother wishing to breast feed her infant. A landmark study demonstrated conclusively the risks of mixed over exclusive breast or formula feeds showed that, at three months of age, 14% of exclusively breast fed babies were HIV positive, compared with 24% of the mixed feeding babies. The EBF babies also fared better than the non-breast fed babies, of whom 18% were HIV positive²¹.

In a study, infants randomized to receive either breast milk or formula, without any other intervention were found to have a cumulative risk of 36.7% vs. 20.2% at 24 months²². In India, during the early years of the HIV epidemic, pregnant women were encouraged to breastfeed their babies according to WHO guidelines and due to concerns of vulnerability of infants given the lack of access to safe drinking water and the prohibitive costs of milk substitutes. The risks of gastroenteritis, pneumonia, septicemia etc are significantly higher in non- breast fed infants. In Pune, it was found that admission to hospital among infants born to HIV positive mothers on replacement feeds was significantly higher²³. In 1996, the Joint United Nations Programme (UNAID) on HIV-1/AIDS recommended that HIV-1 seropositive women in resource poor areas be encouraged to make an informed choice about breast feeding i.e. the risks and benefits of feeding practices should be individualized for each woman.

A number of international clinical trials are evaluating the effect of ARV prophylaxis on the risk of early and late postnatal breast-milk HIV transmission in women who do not require therapy for their own health. In these studies, ARVs are provided to the infected woman solely for reducing breast-milk transmission and are stopped after breastfeeding has stopped. As yet, there are no data on the safety and efficacy of this approach. An alternative approach to prevention of transmission through breastfeeding may be prophylaxis given to the breastfed uninfected infant, and this is being explored in a number of trials. The timing of the postpartum interventions explored in these trials includes ultra-short regimens given in the first week of life to prevent transmission by colostrum or early breast milk. They also include interventions covering the first 6-12 weeks of breastfeeding and interventions that provide ARV prophylaxis to the infant through the first six months of life accompanied by early weaning. At present, HIV positive mothers who choose the breast feeding option should be advised regarding weaning at six months and avoidance of breast feeding if cracked nipples, mastitis or oral thrush (in the neonate) develops.

HIV is heat-sensitive and HIV inoculated into human milk has been shown to be inactivated by pasteurization at 62.5°C for 30 minutes (Holder pasteurization) while preserving the nutritional value and most of the immunological factors in the milk²⁴.

Other interventions

Micronutrient deficiencies are prevalent in many HIV-infected populations, and numerous studies have reported that these deficiencies impair immune responses, weaken epithelial integrity, and are associated with accelerated HIV disease progression. Although low serum vitamin A concentrations were shown to be associated with an increased risk of vertical HIV transmission in prospective cohort studies²⁵, randomized, placebo-controlled trials have reported that vitamin A and other vitamin supplements do not appear to have an effect on HIV transmission during pregnancy or the intrapartum period²⁶.

Caesarean section before the onset of labour has been found to reduce the risk of MTCT. In a large meta-analysis of over 8500 mother-infant pairs, elective caesarean section reduced the risk of transmission by over 50% compared with vaginal delivery²⁷. Transmission was reduced from 7.3% to 2% in women in the analysis who had elective caesarean section and had received long-course antiretroviral treatment. This potential benefit has to be balanced against the risk to the mother: postoperative morbidity has been reported above-average in HIV-infected women, especially infective complications. There is also little information about the additional benefit of elective caesarean section in women receiving highly active antiretroviral therapy with very low viral loads. In contrast, elective caesarean section for reducing MTCT will not be an accessible option in most developing countries, where resources to perform the operation are not available and the prevalence of HIV is very high.

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