Prevention of HIV Transmission From Mother to Child
Transmission of HIV from mother to child commonly occurs during pregnancy (antepartum), during delivery (intrapartum), or through breastfeeding (postpartum). Although evidence is scarce, observational studies have suggested that 25%-45% of children will become infected in the absence of prevention.1 It has further been estimated that about one third of these transmissions occur through breastfeeding,2 while 30% of the remaining occur during pregnancy and 70% during delivery.1
The introduction of the long-course zidovudine (AZT) was considered to be a breakthrough because it was found to reduce transmission by two-thirds in children without breastfeeding.3 Later, a short course AZT regimen was suggested, reducing the cost from about 500 US Dollars (USD) to 50 USD per treatment.4 The cost per treatment was further reduced to about 4 USD per treatment by the introduction of the single-dose nevirapine (sd-NVP). Sd-NVP to mother and infant was found to further reduce intrapartum transmission by roughly 50% compared with the short-course AZT regimen,5 but serious concerns have since been raised about the development of drug resistance.
In high-income settings, mother to child transmission has been reduced to below 2% through a mixture of highly active antiretroviral combination therapies, elective cesarean sections and formula feeding of infants.6 Such comprehensive efforts are clearly superior to short-course regimens like sd-NVP in terms of efficacy and were incorporated into the 2006 World Health Organization (WHO) guidelines for use in low-income settings as well.7 These guidelines advised the programs, as their core, to use highly active antiretroviral therapy (HAART) for mothers who need it for their own health. For women who are not eligible for HAART, the guidelines suggested an AZT-based regimen during pregnancy, delivery, and breastfeeding, with supplementary drugs depending on the history of the woman.8
The most recent WHO guidelines (November 2009) recommend that all HIV-infected women should receive HAART throughout pregnancy and lactation, irrespective of whether or not they need it for their own health.9 This “PMTCT Plus” alternative represents a more intensive level of care than the recommendations of the 2006 guidelines and has been implemented at Haydom Lutheran Hospital (HLH) in northern Tanzania since 2003.10,11 HLH, therefore, represents a good opportunity for evaluation of the recommendations of the recent WHO guidelines.
Although the 2009 WHO guidelines are more ambitious in terms of health improvement for HIV-positive mothers and their children, two-thirds of pregnant women in low-income and middle-income countries are still not receiving even the more basic regimens of antiretroviral prophylaxis.12 In Tanzania, only 28% of reproductive and child health facilities are providing Prevention of Mother To Child Transmission (PMTCT) services.13 Given this situation, it is not obvious that it is time to move from a relatively simple and cheap nevirapine-based single-dose regimen to more expensive but more effective PMTCT strategies including HAART because this could potentially compromise improved coverage in situations of extreme resource scarcity. Furthermore, there is a paucity of evidence from health economics to support the new treatment guidelines. It is, therefore, not known whether the increased use of resources per mother for PMTCT represents good value for money compared with other essential health care interventions with insufficient coverage.
Economic Evaluation Evidence
Although the availability of health economic evidence for PMTCT interventions in sub-Saharan Africa is scarce in absolute terms, it is relatively rich compared with most other areas of health care. A review study by Scotland et al14 found 9 economic evaluations that considered both costs and consequences of interventions addressing mother to child transmission of HIV, and since then, results from a few more recent studies have also been published. A brief review of the evidence is presented below.
The review article revealed evidence evaluating the following 4 drug regimens: ACTG076 regimen (long course AZT), the CDC Thai regimen (short course AZT), the PETRA regimens (combinations of AZT and lamivudine), and the HIVNET012 regimen (sd-NVP). They found that the most recent evaluations reported the most favorable findings due to the development of short-course regimens and declining drug prices.14 These studies had baseline estimates lower than 50 USD per disability adjusted life year (DALY) averted, or they were reported to be cost saving.15-18 The authors observe that the simplicity of the sd-NVP regimen makes it potentially more accessible to sub-Saharan Africa, and this view is reflected in most recent literature.
When a pediatric HIV infection is prevented by PMTCT, there are savings to society in terms of averted medical costs for antiretroviral treatment and medical care. The variety in assumptions, found in the literature, about life-time treatment costs for HIV-positive children reflect different views about the levels of care and price structures of the different settings,14 but also reflect changes in practice between different points of time. Although saved treatment costs were not considered in several articles, they were estimated to be in the range of 276-1209 USD per child infection per year (depending on age) in a South African study.16 Averted treatment costs of 517 USD from birth to death was a key assumption in a study from Mozambique,19 where the authors conclude that sd-NVP is cost saving. A similar observation is made in an article from South Africa, where the total health and welfare costs of an HIV-positive child was between 1919 and 2371 USD. The authors conclude that failing to provide PMTCT means “paying to waste lives.20” All these studies are too early to take full account of the costs and prolonged life expectancy associated with highly active antiretroviral treatment of infected children.
The only study so far to present cost effectiveness results of PMTCT in a Tanzanian setting was done by Sweat et al,21 who at the same time presented results for 7 other sub-Saharan African countries. It is an interesting finding that the cost per DALY averted of sd-NVP is significantly higher in this study compared with the earlier literature. The authors point out that this is because earlier studies ignored or underestimated the costs of enhancing current health systems in Africa to deliver this treatment effectively. They find that, for Tanzania, the annual cost of a national scale up of a comprehensive approach to prevent mother to child transmission including sd-NVP would be some 6.3 million USD. This scale up would avert 2774 infant infections annually, with a cost of 77 USD per DALY averted.21 This study represents important input for health planners in Tanzania, although there are several limitations. First, the study applies the same costing model for all 8 countries. Even though salaries were allowed to vary across settings, this implies rather heroic assumptions about similarities in the organization and structure of the health systems. Second, the study does not account for averted costs of treating infected children. This might have been a plausible assumption at the time of publication, but since then antiretroviral treatment has been more widely implemented in Tanzania and other sub-Saharan Africa settings. Third, the study estimates the cost effectiveness of nevirapine, and does not provide information about whether or not the added costs of a more comprehensive HAART-based regimen (PMTCT Plus) represents good value for money.
The main objective of this study was therefore to model the cost effectiveness of PMTCT Plus compared with sd-NVP. Furthermore, we wanted the model to be based on comprehensive and prospectively collected costing data and include the costs of treating infected children. The project was based at HLH in northern Tanzania, which is a typical rural low-income setting.
PMTCT in Haydom Area
PMTCT of HIV in the Haydom area is organized through 4 different, but interlinked programs: (1) the prevention program, (2) the care and treatment centre, (3) the maternity ward, and (4) the community home-based care program.10 These are described in more detail in the supplemental digital materials (see Supplemental Digital Content 1, http://links.lww.com/QAI/A84).
We use a decision tree model (see Materials, Supplemental Digital Content 1, http://links.lww.com/QAI/A84). to calculate expected costs and outcomes of the 2 prevention alternatives HAART (as described in Supplemental Digital Content 1, http://links.lww.com/QAI/A84) and sd-NVP. As a point of reference, the null intervention (no PMTCT) was also included. A decision tree is appropriate because we use child infections averted as the primary outcome measure and we are not attempting to calculate life-time costs and health benefits for the mothers and babies, in which case a Markov framework would have been more appropriate. We do, also, report costs per DALY averted based on assumptions from the literature.
For all prevention alternatives, the model captures the likelihood of being recruited for preventive treatment either through voluntary testing and counseling (VCT) services or when presenting at hospital for delivery. Subsequently, the model captures the likelihood of HIV transmission taking place depending on whether or not the women have received prevention at different stages of pregnancy, delivery, and breastfeeding. The driver of the incremental effectiveness in the model is that PMTCT Plus addresses transmission risk during pregnancy, delivery, and lactation, whereas sd-NVP only addresses risk related to delivery. A driver of the incremental costs in the model is that PMTCT plus is more costly than sd-NVP. An overview of the input probabilities is given in Table 1 in the supplemental digital materials together with detailed explanation (see Supplemental Digital Content 1, http://links.lww.com/QAI/A84).
Total Costs of PMTCT Plus in the Haydom Area
The total costs of the PMTCT Plus intervention in the Haydom area amount to 122,227 USD for 2007, with the breakdown of activities and cost particulars given in Table 1. Recurrent costs are the most important, representing almost 93% of total costs, whereas annuitized capital costs represent roughly 7%. The CTC department consumes most of the resources, representing 53% of the total program costs. The most important single cause of these costs is the provision of HAART to pregnant women throughout pregnancy and up to 18 months after delivery, with costs for drugs and laboratory services costing 18,238 USD during the year, and other supplies costing 18,964 USD each. The other supplies are related to food and milk support for infected mothers and their babies.
Personnel costs are also an important cost factor within the CTC department. VCT services for testing and recruiting pregnant and lactating women come second in terms of resource demand, representing 36% of the total program costs. Within VCT, personnel costs are the greatest, whereas supplies (test kits and stationery) and transport are also important contributors. CHBC accounts for 7% of the total program costs of PMTCT Plus.
The 2 departments that contribute least to program costs are the maternity ward and the hospital administration, accounting for 3% and 2% of total costs, respectively. This is because the hospital runs a wide range of general and specialized health care programs, and the PMTCT services have been integrated horizontally with the other services. We calculated only the incremental costs of adding the PMTCT services to the other activities, and it might be expected that these costs would be substantially higher with a vertical arrangement commonly applied in other settings.
Intervention Costs and Unit Costs
As mentioned, the total estimated costs of the PMTCT Plus program at Haydom hospital were 122,227 USD for the year 2007. We modeled the costs of PMTCT with sd-NVP and the alternative of providing no PMTCT program by making assumptions about resource demand as explained above. The costs for sd-NVP as a proportion of the costs required for PMTCT Plus are given in the upper half of Table 2. For the sd-NVP set up, we assume that the proportion of administration costs would be the same as for the actually implemented PMTCT Plus program (40%).
Unit costs are based on hospital statistics on the number of women being tested, treated, or who delivered during the year 2007. Table 2 shows that the cost of VCT services was 6.0 USD per woman reached, care and treatment costs 200 USD per woman treated plus 79 USD for the antiretroviral drugs and laboratory costs. The costs of HIV-related testing and counseling during deliveries were 1.2 USD per woman, the cost of community home-based care was 145 USD per woman, whereas administration ranged from 0.2 to 11.3 USD per HIV-positive pregnant woman depending on the choice of intervention.
Cost Effectiveness Results
Base Case Results
The base case results indicate that sd-NVP is dominated by extended dominance in this setting. The expected costs from the model are 8.4, 13.8, and 19.2 USD per pregnant woman for the null intervention, sd-NVP and PMTCT plus, respectively (Table 3). This means that PMTCT plus would be roughly 40% more expensive per woman than the more simple nevirapine regimen in the Haydom area when the likelihood for the different outcomes have been taken into account. Single-dose nevirapine can be expected to avert 0.00051 HIV infections per pregnancy in the catchment area, which translates into roughly 0.013 DALYs. Compared with this, PMTCT plus is roughly 5.2 times more effective, with an expected 0.0027 infections and 0.067 DALYs averted per pregnant woman.
Average cost effectiveness ratios in the base case scenario are 26,826 USD per infection averted (IA) for sd-NVP and 7204 USD per IA for PMTCT plus. The average ratios are calculated for all interventions relative to null intervention, and this process reveals that the sd-NVP is dominated by extended dominance.22 The incremental cost effectiveness of PMTCT plus compared with the null intervention is 4,062 USD per IA. Similarly, the expected incremental cost effectiveness (ICER) of PMTCT plus compared with no PMTCT is 162 USD per DALY (Table 3). It is the ICER after removal of dominated interventions that is the correct basis for the final considerations.22
The 1-way sensitivity analysis shows that the parameter with the greatest influence on model conclusions is HIV prevalence. We compared the outcomes of the HAART-based PMTCT plus intervention with the null intervention, because sd-NVP as explained was excluded because of dominance. In the base case analysis, a HIV prevalence rate of 2% was assumed on the basis of recent estimates from the Haydom area. Allowing the HIV prevalence to increase to 6.6%, which is the most recent national estimate, the incremental cost effectiveness ratio improved from 162 to 60 USD per DALY (Fig. 1). Assuming a lower prevalence rate (1.0%) resulted in the cost effectiveness increasing to 307 USD per DALY and the intervention becoming less economically attractive.
The results were also somewhat sensitive to the baseline rates of HIV transmission, especially the probability of infection during delivery, which resulted in cost effectiveness varying between 134 and 199 USD per DALY for the highest and lowest rates, respectively. Similarly, varying the baseline risk values for transmission during pregnancy and lactation according to Table 1 (see Supplemental Digital Content 1, http://links.lww.com/QAI/A84), resulted in the incremental ratios varying between 154-170 and 151-172, respectively. There was some potential impact from the behavioral parameters, including probability of enrolling to PMTCT for HIV-positive mothers (144-185), and the probability of delivering at hospital for women with unknown HIV status (143 - 187), whereas uncertainty in the probability of accepting VCT had less potential impact on the results (160-163).
Interestingly, the results seem to be less sensitive to uncertainty in the relative risk parameters, with the greatest potential impact for relative risk of HAART during delivery with a range of 156-173 for the most optimistic and pessimistic assumptions, respectively. This was also the case for the cost parameters, except the future treatment costs per HIV infection that varied between 139 and 185 USD per DALY for the sensitivity range explored.
Probabilistic Sensitivity Analysis
Figure 2 show the results from the Monte Carlo simulation in a scatter plot. It can be observed that the overall model uncertainty is significant, especially in terms of effectiveness (DALYs averted). The cost effectiveness acceptability curves (Fig. 3) clearly illustrates that sd-NVP is a dominated strategy (extended dominance) because it is not likely to be the most cost-effective alternative for any level of willingness to pay for health. The figure furthermore illustrates that when the willingness to pay is higher than 162 USD per DALY, the HAART-based PMTCT plus is the most cost-effective alternative.
This economic evaluation is the first to compare directly single-dose nevirapine with a more comprehensive HAART-based intervention to prevent mother to child transmission of HIV in a low-income setting. Our main finding that sd-NVP is a dominated strategy (extended dominance), and that PMTCT Plus with HAART is cost effective provided that the societal willingness to pay for health exceeds 162 USD per DALY, are potentially compelling. These results are, however, based on a single case study, and interpretation for policy recommendations must therefore be made with great caution. The analysis was undertaken in a rural Tanzanian hospital with high standards of care compared with what is usual in the country, and this may affect the relative costs between the alternatives. The PMTCT program is, furthermore, horizontally integrated with regular hospital services at HLH. Although our main conclusions seem to be firm under these circumstances, it remains to be seen whether conclusions would be similar in a vertically organized PMTCT program, which is still common place, or in health facilities with lower clinical standards. It may also be added that results need to be updated as drug regimens change and when better or more relevant clinical evidence becomes available. Especially, we have not included the AZT-based prevention alternatives that are part of the recent guidelines, and more research is needed to explore the cost effectiveness of these relative to sd-NVP and PMTCT Plus.
Our results are sensitive to changes in HIV prevalence rates. The clinical setting is one of the areas in Tanzania with the lowest HIV prevalence, and when we changed the HIV prevalence rate in the sensitivity analysis to the national average of 6.6%, the cost effectiveness improved greatly. Overall, this finding makes sense because VCT programs can be run more efficiently in high prevalence areas, and in a national context, our low prevalence assumption is, therefore, conservative. Our costing study is, however, not a marginal analysis, and we have not studied how changing numbers of patients and costs are affected by economies of scale. The size of the improvement in cost effectiveness in areas with higher HIV prevalence is, therefore, uncertain.
The costs per DALY for sd-NVP are higher in this study compared with those found in most other studies. There are several reasons for this. First, our costing study is more comprehensive than what has been common in the earlier literature. The cost data is collected prospectively in a setting that already has been upgraded to the standard needed to deliver high quality PMTCT services, whereas earlier studies are usually based on models where the costs of enhancing existing health systems have been underestimated.21
We do not include health benefits to mothers in the effect estimation. Although this complies with common practice in PMTCT evaluations, ignoring the mothers undoubtedly underestimates the total health benefits of the program. The principal argument for this choice of method is that it improves the comparability of our study with other economic evaluations of PMTCT interventions. A pragmatic argument is that it would be difficult to find evidence to support an assumption of treatment effects for mothers who are either not eligible on the basis of their own health status or who would not get access to treatment in a situation with insufficient treatment coverage in the absence of a PMTCT program.
One challenge posed by the HIV program at Haydom Lutheran Hospital has been the horizontilization of the originally vertically organized intervention. From the onset of the HIV program in late 2003 until 2006, it became clear that the vertical nature of the program was seriously detrimental to the overall services of the hospital.10 The main reason for this was the structure for donor funding. Funds were linked to specific program components on the basis of the donors' need to justify their involvement. In addition, the national implementation guidelines provided incentive and allowance structures different from those offered to other health services and personnel, generating a strong incentive for the most qualified and leadership personnel to “defect” to the HIV/AIDS program, thus leaving the rest of the hospital at times without qualified personnel when needed. This phenomenon has been discussed more generally by Reich et al.23 In 2006, the hospital started the process of integrating the services, and this process was not fully achieved until 2008. Thus our study was performed on a program, which was in the final stages of this process, and the future level of benefits may, therefore, not have been fully appreciated.
We find that sd-NVP is extendedly dominated by the HAART-based alternative, which implies that the former from a health maximization point of view should be removed from further consideration. For 3 reasons we discourage such a blunt interpretation of our results. First, because this is a single study, we need more research to establish the validity of our finding more generally. Second, our case represents a situation of equity-efficiency trade-off where the overall conclusion is uncertain when also distributional consequences are considered. This is because the most cost-effective alternative (PMTCT plus) is also the most costly, meaning that fewer patients will be able to receive treatment when resources are insufficient for all. This, indeed, is very much likely to be the case in Tanzania and other low-income settings. Finally, we believe the budget implications for a PMTCT plus implementation must be further evaluated and resolved in order for the program to be sustainable.
The study show that PMTCT with a HAART-based PMTCT Plus regimen is more cost effective in a rural setting than the current Tanzanian standard of care with sd-NVP. Although PMTCT Plus is roughly 40% more expensive than sd-NVP, the expected health benefits are 5.2 times greater. The incremental costs effectiveness ratio of the PMTCT Plus intervention is calculated to be 4,062 USD per child infection averted and 162 USD per DALY. This is less than a third of the threshold of one gross domestic product per capita per DALY suggested by the World Health Report 2002.24 According to this standard, implementation of PMTCT Plus in a Tanzanian setting can be seen as highly cost effective.
These results are based on data from a single clinical set-up in a single area combined with evidence from other settings. Although sensitivity analyses indicate that our main conclusions are relatively firm, more evidence on joint costs and health effects of the alternative treatment options are needed to inform a change in national and international treatment guidelines.
We thank the HLH administration and staff for support and assistance during the work. Special thanks go to Mr Suleimani Ginachan Manya who sat with us for many days meticulously going through all the accounts. Without his help, it would not have been possible to write this article. In addition, we thank the staff at the HLH PMTCT of HIV unit for their assistance at all stages of this research. We further thank COSTECH and NIMR in Tanzania for providing ethical clearances and the regional, district and divisional authorities for further research permission. In the final stages of the work, Ole F Norheim, Ingunn M Engebretsen, Asgeir Johannesson, Marius Troseid, and Julia Norman provided valuable comments that improved the quality of the article.
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