Assumptions regarding infant feeding practices in women who are HIV negative or HIV positive but undiagnosed are based on the results of the 1998 Demographic and Health Survey.16 About 87% of these women are assumed to start breastfeeding, and the duration of breastfeeding is modeled using a Weibull distribution with a median of 18 months and a shape parameter of 2. All these women are assumed to practice mixed feeding because exclusive breastfeeding (EBF) was rare before the introduction of PMTCT programs.16,34 Women who were HIV positive at delivery and who practice mixed feeding are assumed to have a fixed monthly probability of transmitting HIV, h1. Breastfeeding HIV-negative mothers are assumed to acquire HIV at the same rate as pregnant women, and for an average period of 3 months after acquiring HIV, are assumed to have a higher monthly probability of transmitting HIV through mixed feeding, h0. The parameter h0 is estimated from studies of the cumulative HIV transmission risk from breastfeeding mothers who have seroconverted (summarized in Table 1), by noting that this cumulative risk can be expressed as
In each year, a proportion of pregnant women are assumed to receive HIV testing, increasing from 3% in 2000 to 92% in 2010 and subsequent years (see Section 1, Supplemental Digital Content 1, http://links.lww.com/QAI/A241). A fraction of those women testing positive start antiretroviral treatment (ART) if their CD4 count is below 200 (or below 350 following the change in South African guidelines in 201035). Of the remaining women who are diagnosed HIV positive, a fraction is assumed to receive single-dose nevirapine, and following changes in guidelines in 2008,36 a fraction of women receiving single-dose nevirapine are assumed also to receive short-course zidovudine. Of the women who are diagnosed HIV positive antenatally, 50% are assumed to avoid breastfeeding completely,37,38 35% practice EBF, and 15% practice mixed feeding.39 The monthly probability of postnatal transmission is reduced if the child receives extended nevirapine prophylaxis, if the mother receives ART or if the mother practices EBF. HIV-diagnosed women who practice mixed feeding are assumed to do so for a median of 7 months. HIV-diagnosed women who practice EBF are assumed to do so for a median of 2 months (up to a maximum of 6 months), after which 30% are assumed to discontinue breastfeeding completely and the remainder practice mixed feeding (ie, continue breastfeeding while introducing complementary feeds), for a median of 7 months.39–41 Following the change in guidelines in 2010,35 a proportion of HIV-diagnosed women who choose to breastfeed are assumed to administer extended nevirapine prophylaxis to their children, with this proportion rising to 80% by 2013. Following the more recent announcement of a phasing out of free provision of formula milk in public clinics, the proportion of HIV-diagnosed women who avoid breastfeeding is assumed to decline from 50% in 2010 to 20% in 2013. Assumptions about vertical transmission rates and the efficacy of PMTCT are summarized in Table 2, and a more detailed description of the model is provided in Supplemental Digital Content 1 (http://links.lww.com/QAI/A241).
Children who acquire HIV are assumed to progress to a state of ART eligibility, after which they may start ART. Rates of progression to ART eligibility and rates of AIDS mortality in ART-eligible children are assumed to depend on age and mode of transmission (perinatal or postnatal), as described elsewhere.42 Numbers of new infections in children and numbers of children in different exposed and infected states are calculated at monthly time steps, starting in 1985. To ensure that the model assumptions regarding mother-to-child transmission (MTCT) and pediatric HIV survival are plausible, the model is fitted to age-specific pediatric HIV prevalence data from national household surveys conducted in 2005 and 2008,60,61 using a Bayesian uncertainty analysis approach. Beta prior distributions are specified to represent ranges of uncertainty around key parameters, and the means and standard deviations of these distributions are included in Table 2. Posterior distributions, representing the ranges of model results consistent with both the observed pediatric HIV prevalence data and the ranges of uncertainty around the input parameters, were simulated numerically using Incremental Mixture Importance Sampling.62
Three possible interventions are considered to reduce vertical transmission from mothers who acquire HIV after their first antenatal visit:
1. Maternal HIV incidence is assumed to reduce by 50% after 2010. A 50% reduction in HIV incidence by 2011 is a target of South Africa's National Strategic Plan,63 and could potentially be achieved in pregnant and breastfeeding women through intensified condom promotion, partner outreach, microbicides, and preexposure prophylaxis.
2. The offer of antenatal screening is assumed to be repeated at 34-week gestation in women who tested negative or did not receive testing at their first antenatal visit, from 2010 onward. This has been recommended in recent PMTCT guidelines,35,36 but implementation has been limited. It is assumed that 80% of women who previously tested negative would accept the offer of retesting,17 and 50% of women who did not receive testing at their first antenatal visit get tested at 34 weeks.
3. Mothers and infants are assumed to be screened for HIV at 6-week immunization visits, from 2010 onward. Although not part of current South African guidelines, this has been proposed by Rollins et al.32 About 92% of mothers are assumed to attend 6-week immunization visits,16 and 66% of women testing positive are assumed to receive their test results.33 Of those women who are diagnosed HIV positive, 50% are assumed to discontinue breastfeeding immediately (this proportion reducing to 20% by 2013), and those who continue to breastfeed are assumed to do so for a shorter period (median 7 months), with 80% administering nevirapine prophylaxis to their infants.
For ease of reference, we use the term ‘recently infected mothers' to refer to women who seroconvert after their first antenatal visit, either during late pregnancy or while breastfeeding.
Age-specific model estimates of HIV prevalence were reasonably consistent with survey estimates, although the model tended to estimate higher HIV prevalence in 2008 than observed in the 2008 survey,42 possibly a reflection of the high rates of test refusal in children.61 Posterior distributions for the MTCT parameters in Table 2 were similar to the prior distributions, except in the case of the probability of MTCT from chronically infected mothers, per year of mixed feeding [posterior mean of 11.6%, 95% confidence interval (CI): 8.4% to 15.7%].
The model estimates that the number of new HIV infections in South African children reached its highest level in 2002, at 94,000 per annum (95% CI: 86,000 to 104,000), and dropped to 57,000 per annum (95% CI: 51,000 to 64,000) by 2008. This incidence is 44% lower (95% CI: 39% to 47%) than the level of pediatric HIV incidence that would have been expected over the same period in the absence of PMTCT (Fig. 2A). The number of new HIV infections in children is projected to drop to 39,000 per annum (95% CI: 34,000 to 43,000) by 2014, after the implementation of the revised 2010 PMTCT guidelines (but not allowing for the additional interventions to reduce transmission from recently infected mothers). This represents a 60% reduction (95% CI: 57% to 63%) in pediatric HIV incidence, relative to what would be expected in the absence of PMTCT.
In 1990, when antenatal HIV prevalence was <1% but HIV incidence was increasing rapidly, an estimated 60% of vertical transmission (95% CI: 55% to 64%) was from mothers who acquired HIV after their first antenatal visit (Fig. 2B). As HIV prevalence in pregnant women increased relative to HIV incidence, the proportion of vertical transmission from recently infected mothers declined, and would have continued to decline in the absence of PMTCT, to a level of 15% (95% CI: 13% to 17%) by 2008 (15,000 of 102,000 infections). However, PMTCT programs have significantly reduced transmission from mothers who were seropositive at their first antenatal visit, while having negligible impact on transmission from recently infected mothers. As a result, the proportion of vertical transmission from recently infected mothers has increased since 2002, rising to 26% (95% CI: 22% to 30%) in 2008 (15,000 of 57,000 infections). The proportion is projected to increase to 34% (95% CI: 29% to 39%) by 2014 (13,000 of 39,000 infections), in the absence of specific interventions to prevent transmission from recently infected mothers.
At all stages in the epidemic, most of the vertical transmission from mothers who have acquired HIV after their first antenatal visit is postnatal transmission (Fig. 3A) because there is more opportunity for maternal seroconversion during the long breastfeeding period than during the relatively short period between first antenatal visit and delivery. This is in contrast to transmission from mothers who are HIV positive at their first antenatal visit, which is predominantly perinatal. Because postnatally infected children are assumed to survive for longer than perinatally infected children, they account for a greater proportion of prevalent HIV (Fig. 3B) than incident HIV (Fig. 3A). The proportion of prevalent HIV in children that is attributable to transmission from recently infected mothers was 30% in 2010 (95% CI: 26% to 35%). This proportion varies substantially by age, from 18% (95% CI: 13% to 22%) in infants to 58% (95% CI: 52% to 65%) in 14-year-olds, in 2010 (Fig. 3D). In 2000, when the epidemic was less mature, fewer HIV infections occurred in older children, but age-specific proportions of pediatric HIV acquired from recently infected mothers were higher (Fig. 3C).
Reducing HIV incidence in pregnant and breastfeeding women by 50% would reduce the number of new HIV infections in children, over the 2010–2015 period, by 16.2% (95% CI: 13.9% to 18.6%). Repeating the offer of HIV testing in late pregnancy would reduce the number of new HIV infections in children by 11.2% (95% CI: 9.5% to 12.7%), and conducting HIV screening in mothers and infants at 6-week immunization visits would reduce new infections in children by 3.5% (95% CI: 2.7% to 4.4%). However, the numbers of HIV infections averted per 1000 HIV tests performed in late pregnancy (7.2, 95% CI: 6.4 to 8.1) and at immunization clinics (1.9, 95% CI: 1.4 to 2.6) are substantially lower than the number of HIV infections averted per test performed at the first antenatal visit (62.5, 95% CI: 55.7 to 70.7), and additional screening after the first antenatal visit would therefore be less cost-effective. If all 3 interventions were introduced together, the average annual number of new pediatric HIV infections over the 2010–2015 period would reduce from 38,000 to 27,000, a reduction of 28% (95% CI: 25% to 31%). Combined with existing PMTCT interventions, this would represent a reduction in the annual number of new HIV infections of 72% (95% CI: 68% to 74%) in 2014, relative to what would be expected in the absence of PMTCT.
These results suggest that mothers who experience HIV seroconversion during pregnancy and breastfeeding contribute substantially to vertical transmission of HIV. The relative significance of this transmission depends on 3 factors. First, the contribution is substantially higher during early-stage HIV epidemics, in which HIV incidence rates are high and HIV prevalence rates are still relatively low; the contribution can be expected to decline as antenatal HIV prevalence rises and adult HIV incidence starts to decline. Second, the relative contribution is higher the greater the extent of PMTCT programs, which have been directed almost exclusively at women who are seropositive at their first antenatal visit. Third, the model simulations suggest that the contribution to postnatal transmission is substantially greater than the contribution to perinatal transmission, and the significance of transmission from mothers who seroconvert after their antenatal screening visit is therefore likely to depend on the average duration of breastfeeding. The median duration of lactation in South Africa is shorter than in most other African countries,64 and the proportion of vertical transmission from mothers who are recently infected could therefore be higher in other African countries. However, access to PMTCT in other African countries is generally more limited than in South Africa,64 which would imply a lower proportion of vertical transmission from mothers who seroconvert during pregnancy and breastfeeding.
This analysis suggests that “virtual elimination” of mother-to-child transmission of HIV is likely to be challenging, even with optimistic assumptions about the future introduction of interventions to prevent transmission from pregnant women who are initially seronegative. Repeated HIV screening in late pregnancy would have some effect on the identification of recently infected women, but most of the modeled benefit of this strategy is because of the diagnosis of chronically infected women who previously refused testing (see Section 4, Supplemental Digital Content 1, http://links.lww.com/QAI/A241). The benefits of HIV screening at immunization clinics, if it were introduced in South Africa, would probably be modest, amounting to a less than 5% reduction in current pediatric HIV incidence. The most effective way to limit transmission from seroconverting mothers is to prevent them from acquiring HIV in the first place, but there is uncertainty regarding the ideal means to achieve this. HIV counseling and testing has generally had negligible impact on behavior in individuals who test HIV negative,65,66 and it is therefore debatable whether condom promotion to HIV-negative pregnant women would substantially reduce HIV incidence. HIV counseling and testing of male partners has been suggested as one strategy for limiting maternal HIV incidence,67 but African studies that have attempted to integrate male partners into antenatal HIV testing have typically managed to test only 10%–20% of partners.68–70 Promising recent evidence71–73 suggests that tenofovir-based products could provide protection against maternal HIV acquisition, but there is currently a lack of evidence regarding the safety of tenofovir use during pregnancy and lactation.74
A limitation of this analysis is that maternal HIV incidence rates have been estimated from the ASSA2003 model, which calculates HIV incidence in pregnant women as a weighted average of age-specific female incidence rates, where weights are numbers of births to HIV-negative women at each age. This does not allow for the possibility that pregnant women may be biologically or behaviorally different from other women at the same age. Some evidence suggests that women may experience heightened susceptibility to HIV during pregnancy75–77 and during the early postpartum period,78,79 although other studies have not confirmed this.80 If the actual maternal HIV incidence rates during pregnancy and breastfeeding are higher than estimated by the ASSA2003 model, our model is likely to underestimate the extent of vertical transmission from mothers who seroconvert during pregnancy and breastfeeding. However, it is also possible that the ASSA2003 model may underestimate the extent of recent reductions in maternal HIV incidence because of inadequate allowance for recent increases in condom usage and HIV testing.81 In a sensitivity analysis to explore the effect of either halving or doubling the rate of maternal HIV incidence in 2008, the proportion of mother-to-child transmission from recently infected mothers changed to 15.4% (95% CI: 13.0% to 17.9%) and 39.8% (95% CI: 35.2% to 44.8%), respectively (see Section 6, Supplemental Digital Content 1, http://links.lww.com/QAI/A241).
A more general limitation is the lack of information regarding several key MTCT parameters. It is possible that feeding practices of HIV-negative and undiagnosed HIV-positive mothers may have changed since the time of the 1998 Demographic and Health Survey, but there is little evidence to show this.61,82 There is also little information on feeding practices in women who have been diagnosed HIV positive and counseled on infant feeding. Since the introduction of the new PMTCT guidelines in 2008 and 2010, there has been little data on the extent to which the changes recommended in these guidelines have been implemented, and the model projections beyond 2008 therefore need to be treated with caution. A recent South African survey found that perinatal HIV transmission rates by 6 weeks were reduced to 3.5% by 2010,83 and this implies a higher level of PMTCT coverage than assumed in our model. Since higher PMTCT coverage implies proportionately greater contributions to vertical transmission from recently infected mothers, our model may therefore underestimate the proportion of vertical transmission in 2010 that was from recently infected mothers. There is also uncertainty regarding the extent to which HIV prevalence data and PMTCT data collected from women attending public antenatal clinics can be generalized to the whole population of pregnant women, some of whom seek private antenatal care or do not seek antenatal care at all. However, the proportion of pregnant women who access public sector antenatal care in South Africa is around 82%,16 and any bias associated with the exclusion of other women is therefore likely to be small.
As efforts to eliminate vertical transmission intensify, it will become increasingly important to focus on transmission from recently infected mothers. Projections that do not take this transmission into account are likely to understate pediatric HIV incidence and prevalence substantially, with implications for the estimation of pediatric ART need and AIDS mortality. Policymakers will need to seek creative solutions to this problem and will need to move toward greater integration of adult and pediatric HIV prevention if this challenge is to be addressed effectively.
L. Johnson thanks the South African Medical Research Council and the William and Flora Hewlett Foundation for funding.
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