Interventions for preventing postnatal mother-to-child transmission of HIV

  • Protocol
  • Intervention

Authors

  • BC Madi,

  • N Smith,

  • V Leroy,

  • TH Horvath,

  • GE Kennedy,

  • F Dabis,

  • GW Rutherford,

  • JS Read


Dr Banyana Madi, Senior Qualitative Scientist, IMMPACT, University of Aberdeen, 12 Westdyke Drive, Elrick, Westhill, Aberdeen, Scotland, AB32 6QR, UK. banyana@bcmadi.com.

Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

The purpose of this systematic review is to collate and assess the evidence of interventions to decrease postnatal MTCT of HIV, and to determine which interventions are most effective in decreasing postnatal MTCT of HIV, increasing overall survival, and increasing HIV-free survival.

Background

By the end of 2005, an estimated 2.3 million children under the age of 15 years (80% resident in sub-Saharan Africa) were living with human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS) (UNAIDS 2006 ). In 2006 alone, approximately 530,000 children were newly infected with HIV and 380,000 died of AIDS (UNAIDS 2006). The vast majority of HIV-infected children acquire the infection through mother-to-child transmission (MTCT) in utero, around the time of labour and delivery, or postnatally through breastfeeding.

Evidence of increased mortality among children of HIV-infected mothers
Children born to HIV-infected mothers have high rates of mortality, regardless of their own infection status (Newell 2004). In a pooled analysis of randomised trials from sub-Saharan Africa, children born to mothers in the advanced stages of HIV infection were at considerably higher risk of death when compared to those of mothers who were at a less advanced stage of the disease (irrespective of the child's HIV infection status), and this association was even stronger for uninfected children (Newell 2004). Also, the timing of acquisition of HIV infection was associated with mortality, as children who were infected before four weeks of age were at higher risk of death during the first 12-24 months after infection than those who acquired infection after four weeks of age (through breastfeeding).

Mother-to-child transmission of HIV
An 'umbrella review' of five Cochrane reviews recently examined the evidence for interventions for the prevention of in utero and intrapartum MTCT (Bond 2007). Two interventions have been shown to be efficacious in the prevention of MTCT of HIV during these periods:

Antiretroviral (ARV) prophylaxis: ARVs given to HIV-infected pregnant women and/or to their infants can prevent MTCT of HIV. (Volmink 2007)

Caesarean delivery before labour and before ruptured membranes ('elective' Caesarean section, or ECS): Performing a caesarean section before labour and before ruptured membranes can prevent MTCT of HIV. (Read 2005)

This systematic review will analyse the evidence of interventions for the prevention of postnatal (breastfeeding) MTCT of HIV.

Postnatal MTCT of HIV (through breastfeeding)

In 2006, the World Health Organization reaffirmed previous recommendations for all HIV-infected mothers to receive counseling, including provision of general information about risks and benefits of various infant-feeding options, and specific guidance in selecting the option most likely to be suitable for their individual situation. It also called for mothers to be supported in their choices regarding infant feeding (WHO 2006).

The benefits of breastfeeding are well recognized and include significantly decreased infant morbidity and mortality rates by providing optimal nutrition, protecting against common childhood infections (such as gastrointestinal and respiratory tract infections), and promoting child spacing (Pebley 1986; Thapa 1988; Yoon 1996; Cesar 1999; WHO Team 2000; Kramer 2001). Breastfeeding is particularly important in resource-poor regions of the world, where limited access to clean water increases the risk of diarrhoea if replacement feeding is used. However, HIV is transmitted through human milk, leading to the dilemma that use of replacement feeding in resource-poor settingswhile protecting the infant against HIV infection could also place the infant at risk of mortality from other infections.

Moreover, mothers opting to feed their children through replacement feeding are stigmatised in many cultures, which greatly complicates adherence to a replacement-feeding regimen (Rankin 2005). They are often assumed to be infected with HIV, leading to HIV-associated stigma, where women may be ostracized and expelled from their families in the case of suspected HIV infection. Even in situations where an HIV-associated stigma does not exist and women have the choice to breastfeed or use replacement feeding, the supplies needed to continually conduct replacement feeding can be sporadic, compromising infant nutrition or resulting in mixed feeding. However, exclusive breastfeeding in itself can be difficult for mothers, especially for those who have responsibilities that take them away from their children during the day. In these instances, a child may receive mixed feedingsbreast milk when with their mothers, and alternative feeding options when being cared for by others.

Shortly after the first report of transmission of HIV through breastfeeding (Ziegler 1985), the U.S. Centers for Disease Control and Prevention (CDC) recommended that HIV-infected women in the U.S. avoid breastfeeding (MMWR 1985), because replacement feeding in the U.S. is safe, affordable, and culturally acceptable. The CDC and the American Academy of Pediatrics (AAP 1995) have continued to recommend counseling HIV-infected women in the United States not to breastfeed or provide their milk for the nutrition of their own or other infants. Avoidance of breastfeeding remains an important component of efforts to prevent MTCT of HIV in the U.S. (Read 1999). MTCT of HIV has been substantially decreased in the U.S. (Lindegren 1999).

However, in areas of the world where breastfeeding is the norm and safe replacement feeding generally is not possible, the enormous and unremitting epidemic of MTCT of HIV continues (UNAIDS 2006). Recommendations for these areas of the world have not been specified, but WHO recommendations are similar to those of the CDC, in that when replacement feeding is acceptable, feasible, sustainable, and safe, HIV-infected mothers should avoid breastfeeding altogether (WHO 2006). Research efforts focused on the continuing problem of breastfeeding transmission in much of the world have yielded additional information regarding mechanisms of HIV transmission through breastfeeding, as well as the timing of and risk factors for such transmission.

Breastfeeding transmission of HIV
Over more than two decades, the understanding of MTCT of HIV through breastfeeding has increased tremendously. Beginning with the earliest clinical evidence (case reports) of breastfeeding transmission of HIV (Ziegler 1985), additional information regarding breastfeeding transmission has come from numerous descriptive, analytic epidemiologic, and laboratory studies (Read 2003). Risk factors for transmission of HIV through breastfeeding have been identified, including the duration of breastfeeding as well as characteristics of the mother, the infant, the breast milk, and the type of breastfeeding.

Duration of breastfeeding
The contribution of breastfeeding transmission to the overall risk of mother-to-child transmission of HIV, and the timing of and risk factors for breastfeeding transmission were analysed in an individual patient data meta-analysis of nine clinical trials of HIV-infected women and their infants, conducted in sub-Saharan Africa (BHITS 2004). Breastfeeding contributes substantially to overall mother-to-child transmission of HIV; of children with known timing of infection, 42% acquired infection through breastfeeding. The cumulative probability of transmission increased as the duration of breastfeeding increased (from 1.6% at three months of age to 9.3% at 18 months of age).

Characteristics of the mother and infant
Characteristics of the mother and infant have been associated with increased risk of breastfeeding transmission of HIV. Maternal factors associated with breastfeeding transmission of HIV include younger maternal age and higher parity, (Miotti 1999) maternal HIV disease stage, and breast abnormalities. More advanced maternal disease stage, as manifested by low CD4+ cell counts, is a risk factor for postnatal transmission of HIV (Semba 1999a; Embree 2000; Pillay 2000; BHITS 2004) along with higher maternal peripheral blood or human milk viral load (Semba 1999a; Pillay 2000; Richardson 2003). An early case report of the temporal association of HIV acquisition by the child of an HIV-infected woman with a breast abscess suggested that the ingestion of inflammatory cells related to the bacterial infection of the breast contributes to breastfeeding transmission of HIV (Van de Perre 1992). Later studies confirmed the association of transmission of HIV through breastfeeding with maternal breast abnormalities such as breast abscesses, mastitis, and nipple lesions. In Kenya, mastitis and breast abscesses were associated with late postnatal transmission of HIV (John 2001). In Malawi, women with increased human milk sodium concentrations consistent with sub-clinical mastitis had higher human milk viral loads than did women without increased human milk sodium concentrations (Semba 1999b). In another study in Kenya, maternal nipple lesions and mastitis were each associated with an increased risk of postnatal transmission (Embree 2000). Oral candidiasis before six months of age is associated with late postnatal transmission (Embree 2000), and results of a study in the Ivory Coast suggested maternal breast abscesses and cracked nipples, as well as oral candidiasis in infants, were risk factors for late postnatal transmission of HIV through breastfeeding (Ekpini 1997). Male gender has been associated with breastfeeding transmission of HIV (BHITS 2004).

Characteristics of breast milk
In addition to higher breast milk viral load, characteristics of breast milk possibly associated with a higher risk of breastfeeding transmission of HIV include the following: lower concentrations of antiviral substances, such as lactoferrin (Harmsen 1995; Swart 1996), lysozyme, secretory leukocyte protease inhibitor (SLPI) (Hocini 2000), and epidermal growth factor (Donovan 1994), as well as lesser specific, local immune responses to HIV. Interestingly, HIV-infected women with sub-clinical mastitis, higher human milk viral loads, and higher rates of mother-to-child transmission had higher human milk concentrations of lysozyme and SLPI than did HIV-infected women without sub-clinical mastitis (Semba 1999). However, SLPI concentrations in human milk have not been found by other investigators to be associated with HIV transmission through breastfeeding (Becquart 1999). It has been suggested that epidermal growth factor in colostrum helps to make the gastrointestinal tract less permeable to viral infection (Donovan 1994). Higher mother-to-child transmission of HIV has been associated with lower human milk concentrations of secretory immunoglobulin A and immunoglobulin M during the first several weeks of life in some, (Van de Perre 1993) but not all, studies (Becquart 2000).

Type of infant feeding
Methods of breastfeeding, such as exclusive or mixed feeding, and their association with HIV transmission, have also been studied. In South Africa, data from a randomised clinical trial of vitamin A supplementation to prevent mother-to-child transmission were reanalysed to evaluate a possible association between feeding patterns among infants of breastfeeding HIV-infected mothers and mother-to-child transmission (Coutsoudis 1999; Coutsoudis 2001). In this study, breastfeeding was categorised as exclusive or mixed (i.e., without or with water, other fluids, and food). Women who chose to breastfeed were counselled to consider exclusive breastfeeding. By 15 months of age, children who ever breastfed were more likely to have become HIV-infected than were children who never breastfed. Of children who ever breastfed, those who exclusively breastfed until at least three months of age, but no longer than six months of age, had a lower estimated transmission point estimate than did those with mixed feeding. It was proposed that contaminated fluids and foods given to infants with mixed breastfeeding damaged the bowel and facilitated the entry of HIV into tissues. Subsequent studies, stimulated by this hypothesis-generating study, have confirmed that exclusive breastfeeding is associated with a lower risk of mother-to-child transmission of HIV (Iliff 2005; Coovadia 2007; Sinkala 2007).

Benefits of breastfeeding
. . . .

Interventions that may prevent transmission
Because breastfeeding transmission of HIV does occur, and because avoidance of breastfeeding is impossible in many settings, identification of risk factors for MTCT of HIV through breastfeeding has been important in order to design interventions to prevent such transmission. There are several potential interventions to prevent breastfeeding transmission of HIV. These include decreasing the duration of exposure to breast milk (complete avoidance of breastfeeding, early weaning), decreasing maternal infectivity (lowering viral load in breast milk), addressing factors affecting the transfer of virus from mother-to-child, and improving infant's defences against HIV.

Decreasing the duration of exposure to breast milk

Complete avoidance of breastfeeding
Complete avoidance of breastfeeding would be an obvious option to prevent HIV transmission through breast milk. However, many issues, including feasibility (clean water), affordability of formula and formula-feeding supplies, cultural acceptability, and the overall nutritional status of the child must be considered.

Early weaning
In those circumstances where complete avoidance of breastfeeding is not possible, early weaning from breastfeeding would decrease a child's exposure to breast milk and HIV infection. Again, the issues of feasibility, affordability, cultural acceptability, and nutritional status must be considered. Since the risk of morbidity and mortality associated with replacement feeding was believed to decline after a child's first six months of life, it was considered possible to wean a child off of breast milk and supplement his/her diet with other forms of nutrition (VanDerslice 1994). However, several studies in sub-Saharan Africa have now demonstrated significant morbidity associated with early weaning (Kafulafula 2007, Kourtis 2007, Onyango 2007, Thomas 2007), thus calling for more caution in recommending early weaning for HIV-infected women in resource-poor settings.

Decreasing maternal infectivity (lowering viral load in breast milk)
Studies investigating ways to decrease the viral load in breast milk, either through antiretrovirals for HIV-infected mothers or through the treatment of breast milk with chemical agents or heat are also underway. Some ongoing studies are exploring the efficacy of different antiretroviral drugs, administered over varying lengths of time to breastfeeding infants (Read 2003). Other studies are looking at the treatment of human milk, either through chemical agents or heat to inactivate HIV. Some of these interventions include treating breast milk with microbicidal agents before giving to a child, or even treating breast milk through pasteurisation. It is still to be determined what effect these interventions may have on the final composition of the milk, and to what extent the treatment will have to deactivate HIV.

Addressing factors affecting the transfer of virus from mother-to-child
The education and counselling of mothers are also important factors in preventing postnatal MTCT of HIV. Having an understanding of proper breastfeeding techniques can help mothers mitigate or quickly treat breast abnormalities associated with HIV transmission. The same holds true for infant candidiasis. Educating mothers regarding the importance of exclusive breastfeeding in situations where complete avoidance of breastfeeding is not an option may also be beneficial, and designing an intervention with an emphasis on education and behaviour change may increase both the initiation and duration of exclusive breastfeeding.

Improving an infant's defences against HIV infection
Improving infants' defences is yet another potential way to prevent mother-to-child transmission. It has been hypothesised that passive immunisation with HIV immune globulin may decrease mother-to-child-transmission, and a randomised clinical trial is underway in Uganda. Other studies are evaluating the safety and immunogenicity of active HIV vaccines in infants (Biberfeld 2002).

Objectives

The purpose of this systematic review is to collate and assess the evidence of interventions to decrease postnatal MTCT of HIV, and to determine which interventions are most effective in decreasing postnatal MTCT of HIV, increasing overall survival, and increasing HIV-free survival.

Criteria for considering studies for this review

Types of studies

Randomised controlled trials, and cohort studies of interventions to decrease breastfeeding transmission of HIV and/or increase HIV-free survival, and providing at least an 18-month folow-up, will be included in the review.

Types of participants

HIV-infected mothers and their children.

Types of intervention

Interventions specifically designed to prevent transmission of HIV through breastfeeding.

Types of outcome measures

Primary: in children, HIV-free survival and HIV infection
Secondary:
Children: Death, severe morbidity, growth
Mothers: Social acceptability of the intervention; fertility

Search methods for identification of studies

See: Unavailable methods used in reviews.

See: Cochrane HIV/AIDS Group search strategy.

A comprehensive, unbiased search strategy will be developed to ensure that all relevant studies are screened for inclusion in the review. We will attempt to identify all relevant studies, regardless of language or publication status (published or unpublished, in press or in progress).

Specific search strategies will be used to identify eligible randomised controlled trials or review articles in the following databases:

  • CENTRAL

  • PubMed

  • EMBASE

  • LILACS

  • AIDSearch

Abstracts from relevant HIV/AIDS conferences, reference lists of all relevant articles obtained (including those from previously published reviews), and clinical trial registers (www.clinicaltrials.gov and www.controlled-trials.com) will be screened for potentially relevant articles or studies in progress. We will also contact research organisations and experts in the field for unpublished and ongoing studies.

Methods of the review

1. Selection of studies: Titles, abstracts, and descriptor terms of the electronic search results will be screened independently by two or more authors for relevance, based on the types of participants, interventions, outcome measures, and study design. Full text articles of all selected abstracts will be obtained, and an eligibility form will be used to determine final study selection. These will be also assessed for eligibility in more detail, and classified according to the review objectives. More detailed data extraction will then take place using a second standardised data-extraction form, with discrepancies resolved by consensus. If consensus cannot be reached, the third author will be the final arbiter.

2. Data extraction: For all selected studies, data will be extracted independently by two authors, using a standardised data-extraction form. Any disagreements will be adjudicated by a third author. Should there be missing or inadequate data, attempts will be made to obtain the data by contacting authors. The following information will be gathered from each included study:

  • administrative details: identification; author(s); published or unpublished; year of publication; year in which study was conducted; details of other relevant papers cited

  • details of study: study design; type; duration and completeness of follow-up; country and location of the study; number of participants

  • characteristics of participants: inclusion and exclusion criteria; diagnostic criteria for HIV in mothers and infants; modes of feeding with their definitions (exclusive breastfeeding, predominant, breastfeeding, formula feeding or mixed).

  • details of intervention: types and doses of drugs used; duration of therapy; where/setting; context, etc

  • details of outcomes: primary and secondary outcomes; effectiveness of intervention studied

  • details of study ethics: informed consent obtained for participation; approving institution(s)

3. Quality assessment: The methodological quality of included studies will be evaluated independently by two authors, and the methodological quality of included studies will be assessed using appropriate quality evaluation tools (Jadad for RCTs, QUOROM for systematic reviews, and STROBE and Newcastle-Ottawa for observational studies).

  • The likelihood of selection bias will be assessed by evaluating the method of allocation sequence generation and the adequacy of allocation concealment.

  • Performance bias will be assessed by establishing if any additional interventions happened, as well as looking at the presence or absence of blinding.

  • Detection bias will be assessed by evaluating the method of outcome assessment and whether the same method of ascertainment was used in both groups, as well as assessing blinding.

  • Attrition bias will be assessed by looking at the follow-up to see if at least 80% of participants in all groups were included in the final analysis and also whether the description of those not included is suggestive of bias.

4. Data analysis: Experimental and observational studies will be examined separately. If possible, a meta-analysis will be undertaken to measure the appropriate measure of effect and 95% confidence intervals. For the primary outcomes, relative risks will be computed. Seeing that heterogeneity is expected between the included studies, a random-effects model will be used. The Chi-square test for heterogeneity will be computed with a p-value of 0.10 to determine statistical significance. The Ι2 statistic will be computed to quantify inconsistency across studies. For continuous data, mean differences will be used; however, if the outcome was measured using scales, and multiple scale-use is anticipated, standardised mean differences will be computed.

In cases where meta-analysis is not possible and/or appropriate, narrative synthesis will be provided. Sensitivity analysis will be performed to assess the impact of study quality. Subgroup analysis will be conducted by type of intervention, type of population (education, SES, rural vs. urban, as well as other pertinent factors, as determined by the authors).

5. Outcomes of interest:
The primary outcome is the HIV-free survival at various points of time from birth to at least 18 months of age.
Secondary outcomes include estimated rate of MTCT of HIV at different points in time, mortality and morbidity, growth and maternal social acceptability.

Potential conflict of interest

None of the authors have any conflict of interest.

Sources of support

External sources of support

  • No sources of support supplied

Internal sources of support

  • No sources of support supplied

Ancillary