Introduction

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Whereas paediatric HIV infection is on the verge of being eliminated in the United States, in sub-Saharan Africa it has become a common cause of admission to hospital and a major contributor to childhood mortality.¹ The results of recent studies showing the efficacy of short course antiretroviral treatment for the prevention of vertical transmission of HIV in breastfed and formula fed infants has led to debate around their more widespread introduction internationally.^2-4

For some years now, developed countries have had in place cost effective methods to prevent the vertical transmission of HIV.⁵ In developing countries, however, these interventions have not been offered on a routine basis. The main reason for this is the perceived high cost of transmission prevention programmes rather than lack of evidence of effectiveness. Interventions that seem to reduce vertical transmission in developed and developing countries include substitution of formula feeding for breast feeding⁶ and administration of antiretroviral agents to mother and child around the time of birth. ^{2-4 7-9} Caesarean section significantly reduces vertical transmission,¹⁰ although cost effectiveness is not established even in developed countries¹¹ and it is unclear how feasible elective caesarian sections are in areas with poor resources. Other interventions, such as the use of vaginal antiseptics before delivery and the administration of vitamin A with or without micronutrients, have yet to be conclusively evaluated. ^{12 13}

For policymakers the health and economic benefits of avoiding childhood HIV infection need to be balanced against the costs of implementing vertical transmission prevention programmes and any adverse effects that may be incurred through such programmes.¹⁴ South Africa is no exception. With more than 1 in 5 women attending antenatal clinics nationally testing positive for HIV in 1998 (Department of Health press release, February 1999), both the benefits of infection avoided and the costs of intervention are likely to be considerable and hence the penalty for wrong decisions substantial. Many factors need to be taken into account in considering this type of intervention; some of these are outlined in the box.

This study sought to develop a method to inform such decisions by using a mathematical simulation model approach. The study objective was to compare the likely cost effectiveness of different strategies to prevent vertical transmission such as antiretroviral treatment and artificial feeding alone and in combination in an urban working class population in South Africa. While we believe that the model can be generalised to many settings globally, it was applied to this particular context because of easy availability of verifiable data and the immediate requirements of policymakers in South Africa.

Several evaluations of cost effectiveness in developing countries have been undertaken recently. Marseilles and others¹⁵ and Mansergh et al¹⁶ did not assess combined interventions and the latter study used HIV infection rather than mortality as its outcome of interest. Mansergh et al¹⁶ and Wilkinson et al¹⁷ estimated cost effectiveness before the efficacy of the short course treaments had been shown. The regimens were therefore more costly and more difficult to implement than short course regimens, which have now been proved to be effective.

	Methods

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We applied a Markov chain simulation model to the problem outlined above. This approach attempts to replicate the natural course of transmission and disease by simulating transitions between discrete disease states. In this case, unborn children were assumed to progress from uninfected to infected to dead states. The rates of transition between these states were determined by environmental and interventional parameters specified in the model. A cohort of 20 000 pregnancies occurring over a period of 1 year, reflecting the approximate number of births in the community studied, were simulated. The children from these pregnancies born to HIV positive women were followed either until their predicted age of death according to current life expectancy data (for HIV negative children) or until their death due to HIV infection (for HIV infected children). Costs, morbidity, and mortality were simulated for the birth cohort with seven different intervention strategies and a control strategy of no intervention (box). In addition, combinations of the more favourable interventions were modelled. Model transitions occurred on a monthly basis for the first 9 years of life and then on an annual basis until death. Model hazard functions generally followed Weibull distributions that were fitted to best available data from settings similar to the one under study.

The model was applied to the Soweto community, a black, urban, working class population of about 1 million people located south west of central Johannesburg. The community is served mainly by a single public hospital, the Chris Hani Baragwanath hospital, which has over 3000 beds. As far as possible all data were drawn to reflect this community and the hospital serving it. Table 1 outlines the main model assumptions, and the full set of model inputs are detailed in the BMJ website version of this paper. All costs are expressed in US dollars (converted for South African rands at the 1998 rate of R6=$1) and where necessary £ (at $1.5=£1). More details on the derivation of cost data are given elsewhere.²⁶ Rates of use and associated costs of health care for HIV infected children were estimated from data recorded on all paediatric admissions to the hospital between 1992 and 1997, during which time the proportion of paediatric admissions infected with HIV increased from 2.9% to 20%.²⁷ The denominator population of HIV infected children to which these utilisation and cost data applied was calculated by using a simple survival model and data from serology surveys of antenatal clinics from the preceding 7 years.

The cost effectiveness of each intervention was calculated relative to the control group as (IC+NCHC)/(LS*LELL*LE); where IC=intervention costs, NC=healthcare costs because of additional morbidity in formula fed children not infected with HIV, HC=costs of HIV related care avoided by preventing infections, LS=lives saved by prevention of HIV infection, LL=lives lost because of formula feeding in children not infected with HIV, and LE=life expectancy.

Results were obtained in terms of costs per life year saved. Future costs and benefits were discounted at a rate of 5% per year.²¹ Health benefits and losses due to morbidity avoided or caused were ignored as their effect was negligible compared with that of mortality. Likewise, costs to family members of caring for sick children were not included because no data were available.

	Results

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One of the advantages of a Markov simulation approach is that it allows simultaneous estimation of likely costs and effectiveness associated with a given intervention.³² For simplicity, however, results are described here as effectiveness, costs, and cost effectiveness.

Effectiveness of interventions
Effectiveness was measured in terms of discounted life years saved and deaths averted.These represented the difference in years of life achieved and deaths, respectively, between the control and intervention populations. Figure 1 shows the net number of discounted deaths averted for each year after birth of the simulated cohort. The ACTG076 regimen is the most effective antiretroviral regimen but is only marginally more effective than the CDC-Thai regimen because of relatively lower levels of uptake attributable to the long and complicated administration requirements of the ACTG076 regimen. Whereas the number of lives saved from prevention of prepartum and intrapartum HIV peak in the first year of follow up, the net deaths prevented by formula feeding interventions tend to be later on (the model suggests that they peak in year 2). This is partly because of the later onset of HIV disease and partly because lives saved by formula feeding in the first year are offset by lives lost due to the lack of protective effect of breast milk in HIV negative children. The model suggests that options that recommend breast feeding early on, with a change to formula feeding after 3 or 6 months, save the least number of lives as most HIV transmission through breast milk seems to occur early on. ^{2 33 34}

View larger version (20K): [in this window] [in a new window]   Fig 1.    Discounted deaths prevented by year after birth and mode of intervention

Costs
The costs of administering each of the interventions were estimated for 20 000 pregnancies over a 1 year period. They include both annualised capital and recurrent costs and have been broken down into the costs of screening and counselling (which were essentially the same for all interventions) and the costs of the intervention itself, which included the costs of antiretroviral drugs, additional monitoring tests required, formula feeds, bottles, and staff time required for administering interventions. Figure 2 shows these costs, together with costs incurred because of increased incidence of diseases other than HIV caused by decreased breast feeding and savings due to illness prevented from HIV infection. The ACTG076 regimen is the most costly strategy by a considerable margin, and more than 80% of costs are due to expenditure on antiretroviral drugs and their administration. All of the strategies involving formula feeding from birth result in considerable costs because of disease other than HIV. Cost savings due to HIV infection averted are in line with relative effectiveness estimates.

View larger version (22K): [in this window] [in a new window]   Fig 2.   Costs of interventions, HIV cases prevented, and disease other that HIV caused by each intervention for simulated cohort of 20 000 pregnancies ($1.5=£1)

Cost effectiveness
The cost effectiveness of each of the interventions is given in table 2. The World Development Report suggested that interventions costing less than $100 (£67) per life year saved are cost effective for middle income countries.²¹ Cost effectiveness is estimated for individual and combined interventions. The CDC-Thai regimen alone and the CDC-Thai combined with formula feeding from birth at least pay for themselves in terms of costs of care avoided. The delayed formula feeding strategies do not seem to be particularly cost effective. The intrapartum and postpartum PETRA regimen is less cost effective than the CDC-Thai regimen but in overall terms still represents good value for money. It does not require antiretroviral treament until labour and might thus be the most feasible option when women present late in pregnancy or in labour.

	Discussion

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We have attempted to develop a generally applicable simulation model for assessing the effectiveness and cost effectiveness of interventions to prevent mother to child transmission of HIV and to apply this to a particular context with which we were familiar. We are confident that administration of a low cost antiretroviral regimen or advocating formula feeding for infants of HIV infected women, or both, would save lives and, in many cases, save money as well. Provision of formula feed seems to be relatively expensive given the modest increase in effectiveness that it generates. The delayed formula feeding strategies and the ACTG076 regimen have little to recommend them in South Africa. By comparison, however, a recent report estimates that triple antiretroviral treament for HIV disease costs about $10 000 (£6667) per life year saved, adjusted for disability.³⁵

Affordability and feasibility
Aside from cost effectiveness, issues to consider in the introduction of antiretroviral interventions into health systems include affordability, availability of human resources, and infrastructure, equity, and acceptability. It has been estimated that the cost of setting up and running a programme to provide the CDC-Thai regimen to HIV infected women in South Africa at a national level is less than 0.5% of the health budget.²⁶ Combined with our assessment that the intervention is likely to be cost saving, and the enormous social, economic, and health system burden imposed by having to care for sick children infected with HIV, such absolute cost levels tend to refute the claim of Wilkinson et al that strategies to prevent transmission of HIV are unaffordable in South Africa.¹⁷

Generalisation of results
The generalisability of our results is best illustrated by sensitivity analyses. Settings with low rates of HIV infection would seem to be the most obvious relative contraindication to intervention for economic reasons. Elimination of breast feeding in settings with high infant mortality or where there is a strong protective effect of breast feeding would not be recommended as more deaths would be caused than saved by formula feeding. We believe, however, that regardless of setting women who test positive for HIV during pregnancy should be given information to enable them to make an informed decision as to how to feed their infants. The antiretroviral interventions were generally more robust in the face of changes in the various settings, with or without formula feeding. Recently published results from an antiretroviral trial in breastfeeding women support this finding.² The scope of this paper does not allow description of all possible combinations. We would encourage anyone interested in applying the model to local conditions to contact the authors directly.