Advertisement
Research Article

The Cost-Effectiveness of Directly Observed Highly-Active Antiretroviral Therapy in the Third Trimester in HIV-Infected Pregnant Women

  • Caitlin J. McCabe,

    Affiliation: Child Health Evaluative Sciences, Research Institute of the Hospital for Sick Children, Toronto, Ontario, Canada

    X
  • Sue J. Goldie,

    Affiliation: Department of Health Policy and Management, Harvard School of Public Health, Boston, Massachusetts, United States of America

    X
  • David N. Fisman mail

    david.fisman@gmail.com

    Affiliations: Child Health Evaluative Sciences, Research Institute of the Hospital for Sick Children, Toronto, Ontario, Canada, Department of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada

    X
  • Published: April 13, 2010
  • DOI: 10.1371/journal.pone.0010154

Abstract

Background

In HIV-infected pregnant women, viral suppression prevents mother-to-child HIV transmission. Directly observed highly-active antiretroviral therapy (HAART) enhances virological suppression, and could prevent transmission. Our objective was to project the effectiveness and cost-effectiveness of directly observed administration of antiretroviral drugs in pregnancy.

Methods and Findings

A mathematical model was created to simulate cohorts of one million asymptomatic HIV-infected pregnant women on HAART, with women randomly assigned self-administered or directly observed antiretroviral therapy (DOT), or no HAART, in a series of Monte Carlo simulations. Our primary outcome was the quality-adjusted life expectancy in years (QALY) of infants born to HIV-infected women, with the rates of Caesarean section and HIV-transmission after DOT use as intermediate outcomes. Both self-administered HAART and DOT were associated with decreased costs and increased life-expectancy relative to no HAART. The use of DOT was associated with a relative risk of HIV transmission of 0.39 relative to conventional HAART; was highly cost-effective in the cohort as a whole (cost-utility ratio $14,233 per QALY); and was cost-saving in women whose viral loads on self-administered HAART would have exceeded 1000 copies/ml. Results were stable in wide-ranging sensitivity analyses, with directly observed therapy cost-saving or highly cost-effective in almost all cases.

Conclusions

Based on the best available data, programs that optimize adherence to HAART through direct observation in pregnancy have the potential to diminish mother-to-child HIV transmission in a highly cost-effective manner. Targeted use of DOT in pregnant women with high viral loads, who could otherwise receive self-administered HAART would be a cost-saving intervention. These projections should be tested with randomized clinical trials.

Introduction

Mother-to-child transmission is the most common cause of pediatric human immunodeficiency virus (HIV) infection in North America. United States surveillance data identified 139 newly recognized HIV infections in children of mothers with HIV infection in the U.S. in 2007; over 9,500 children with likely vertical acquisition of HIV infection have developed AIDS since the HIV epidemic began [1]. Maternal viral load in the third trimester of pregnancy is a strong predictor of risk of HIV transmission to the newborn, and its reduction through the use of highly-active antiretroviral therapy (HAART) appears to markedly reduce the risk of peripartum HIV transmission [2], [3], [4], [5].

Recognition of the large potential impact of maternal HIV replication on transmission has resulted in revision of U.S. and European guidelines on antiretroviral use in pregnancy [6], [7], [8], [9]. These guidelines have long advocated the use of HAART in pregnancy for prevention of transmission, and HAART is now the standard of care for all pregnant HIV-infected women [6]. Adherence to a HAART regimen predicts suppression of viral replication and reduces the potential for emergence of resistant viral strains [10], [11], [12], [13]. Drug adherence is suboptimal in up to one-third of HIV-infected women of childbearing age [14], [15], [16], [17], notwithstanding increases in HAART compliance during pregnancy; mother-to-child transmission still occurs in 1–3% of infants born to HIV-infected women receiving antiretroviral treatment [17]. As low adherence to anti-retroviral therapies is significantly associated with mortality and increased risk of mother-to-child transmission [16], [17], it is important to establish other means of improving adherence in this high-risk group in order to improve clinical outcomes in both mothers and their infants.

Directly observed therapy (DOT) is used in the treatment of tuberculosis to enhance the likelihood of treatment success and minimize the emergence of drug-resistant microbes, and has been proposed as a means of improving adherence to HAART [18], [19]. With HIV, unlike tuberculosis, disease duration is life-long, and medications must be given daily, making the routine use of directly observed HAART problematic. Recent randomized trials have demonstrated significant reductions in viral load in individuals receiving DOT for HIV infection, although this response may not be durable after discontinuation of DOT [20], [21], [22]. Nonetheless, in prisons and community-based settings, the use of DOT for HIV infection has been associated with a reduction in viral burden of 1 to 2 log, even in antiretroviral-experienced individuals [19], [20], [23], [24], [25], [26].

The third trimester of pregnancy may present a unique opportunity for use of directly observed HAART in that the time horizon is limited. In addition to virologic suppression for the prevention of mother-to-child transmission of HIV, directly observed HAART could preserve the future potency of antiretroviral drug classes by limiting emergence of resistance in pregnant women taking these medications solely to prevent transmission. Furthermore, DOT could potentially be an economically attractive intervention, since, if successful, downstream medical costs associated with pediatric HIV infection will be prevented.

The small number of perinatally infected infants makes it challenging to study the impact of DOT-HAART for prevention of perinatal HIV transmission in the context of a prospective, randomized trial; in the absence of such a trial, simulations that aggregate the best available data may be a useful tool to optimize policy under uncertainty. Our objective was to use a simulation model to project the costs and clinical benefits that would be expected to result from the use of DOT in women receiving HAART in the third trimester of pregnancy.

Methods

The Model

We constructed a probabilistic model of HIV infection in pregnancy to project the impact of directly observed HAART on vertical HIV transmission by HIV-infected women receiving treatment by the 3rd trimester of pregnancy (before 28 weeks gestation) according to current U.S. Department of Health and Human Services guidelines [6] (Figure 1), with some proportion of these women having started HAART prior to pregnancy for their own health, and some proportion starting within the first two trimesters of pregnancy with the goal of preventing mother-to-child HIV transmission. Clinical and cost outcomes were projected for a hypothetical cohort of women with asymptomatic HIV infection and CD4-positive lymphocyte counts >200 copies/ml.

thumbnail

Figure 1. Simplified Depiction of Model Tree Structure.

Pregnant women with HIV infection enter the third trimester of pregnancy already on highly-active antiretroviral therapy, with or without direct observation. Round “nodes” represent chance events, while squares represent clinical decisions. Women either experience preterm or term delivery, with a viral load (VL, in copies/ml) that is a function of baseline viral load, effectiveness of antiretroviral drugs, and the availability of directly observed therapy. For both detectable and undetectable viral load responses, a proportion of women receive emergency Caesarean sections. Delivery may otherwise be by elective Caesarean section, or by vaginal delivery. Vaginal delivery is an option only in women with low viral loads on antiretroviral therapy. Health outcomes in the infant are predicted by prematurity (not shown) and the occurrence of mother-to-child transmission.

doi:10.1371/journal.pone.0010154.g001

Women receiving HAART enter the model in the 3rd trimester of pregnancy. We assumed that all transmission occurs in the third trimester of pregnancy or in the peripartum period, and that the probability of transmission is conditional on the maternal viral load at the time of parturition. We incorporated the risk of preterm birth and the subsequent elevated risk of neonatal death, and the relative risks associated with emergency and elective Caesarean section and vaginal delivery. We assumed all infants would be formula-fed, making acquisition of HIV through breast feeding unlikely [27], [28].

Strategies

We used our model to project downstream costs and consequences associated with self-administered HAART and directly observed HAART. For both strategies we assumed patients would receive otherwise standard obstetrical management. HAART was assumed to consist of a combination of two nucleoside reverse transcriptase inhibitors (excluding the combination of didanosine and stavudine) and one or two viral protease inhibitors, with the regimen dosed one or two times daily [6]. We assumed that non-nucleoside reverse transcription inhibitors would not be routinely used for longitudinal therapy in the third trimester [6]. Although current guidelines recommend that all women receive combination antiretroviral therapy in pregnancy, for their own health and/or to prevent vertical transmission [6], we added a hypothetical “no HAART” arm by removing the virological benefits and potential toxicity of HAART, in order to evaluate the cost-effectiveness of both antiretroviral strategies relative to no treatment.

DOT was assumed to consist of daily home visits by a trained public health worker, with observation of the first dose of antiretroviral drugs. If a second daily dose was required, it would be self-administered, as described elsewhere [19]. Standard obstetrical management was considered to consist of monthly visits in the third trimester. Elective Caesarean section delivery was assumed to occur before the rupture of membranes and onset of labour, and was associated with a reduced risk of HIV transmission. Emergency Caesarean delivery was operative delivery after the rupture of membranes and/or onset of labor, and was not associated with a reduced risk of transmission. We assumed that elective Caesarean section was performed in women with viral loads >1,000 copies/ml at term not requiring emergency Caesarean section [6]. Where viral load was <1,000 copies/ml at term and emergency Caesarean section was not required, women could receive either elective Caesarean section or a vaginal delivery. We explored the costs and benefits associated with targeted use of DOT among certain subgroups of women.

Parameterization and Calibration

Probabilities and ranges used in the model were derived from published medical literature obtained through keyword searches on MEDLINE, and through consultation with expert clinicians involved in treatment of pregnant women with HIV infection (Table 1). Individual women's baseline viral load “set points” (i.e., the approximate viral load that would be expected in that individual in the absence of antiretroviral therapy [29]) were drawn at random from a log-normal distribution. The baseline viral load distribution was constructed using viral loads observed in a cohort of 180 antiretroviral-naïve men [30], and reduced by 0.25 log to account for the possibility that viral set point is lower in women [31]. The impact of self-administered HAART was simulated by reducing the baseline viral load using data on the effectiveness of HAART from the Women's Interagency HIV Study (WIHS) [32]. In women assigned to DOT, viral load was reduced again by a log quantity drawn randomly from a triangular distribution, to simulate the increase in adherence reported in association with directly observed HAART [19], [23], [24], [25]. In the base case, we assumed that toxicity secondary to HAART in the developing infant would not be enhanced by directly observed HAART.

thumbnail

Table 1. Selected Model Variables.

doi:10.1371/journal.pone.0010154.t001

To ensure model validity, we calibrated parameters to so that outcomes would approximate those observed in a 2005 European Collaborative Study that showed the effectiveness of HAART in preventing mother-to-child HIV transmission in a cohort study of over 4000 mother-child pairs [33]. We calibrated values for the proportion of women with a viral load <200 copies/ml and the probability of vertical transmission at all viral loads, and we empirically inflated the rates of Caesarean sections (both emergency and elective) and premature births to more closely match the European study's proportions.

Our primary outcome of interest was the quality-adjusted life expectancy (QALY) of infants born to women with HIV infection. Quality-adjusted survival estimates in HIV-infected children incorporated patient-derived, preference-based utility measures [34], in combination with survival estimates reported for pediatric populations and (because most infants will survive to adulthood) adult populations since the advent of HAART [34], [35], [36], [37]. Intermediate outcomes of interest included the number of Caesarean sections performed, and the number of HIV infections in infants under each strategy.

We estimated costs from a societal perspective, including future healthcare costs associated with new HIV infections in infants [38], [39], [40], [41], [42], [43], [44]. The cost of delivery and direct observation of antiretroviral therapy was assumed to be equivalent to that described for tuberculosis-related directly observed therapy [45], [46]. All costs were converted to 2008 U.S. dollars using the Consumer Price Index for Medical Care Services [47], and future costs were discounted using a 3% annual rate in the base case [48].

A health care intervention is considered to be “cost-saving” when it costs less but provides incremental benefit relative to a competing intervention; “highly cost-effective” when it costs less than the GDP per capita; and “cost-effective” when it is between one and three times a country's GDP per capita [49]. A cost-saving intervention is always preferred to competing programs or strategies [49], [50].

Simulations

We generated estimates of costs and consequences of competing strategies through a series of Monte Carlo simulations. Such simulations utilize a random-number generator to create unique, simulated individual patients, and move them through a series of chance events over time [51], [52]. A running tally of outcomes, costs, and events is recorded, with the creation of simulated cohorts that can be compared to one another. Unless otherwise stated, results presented here are each based on five thousand simulations of 200-person clinical trials, with 100 women randomized to directly observed HAART and 100 women randomized to self-administered HAART in each trial.

Sensitivity Analyses

We evaluated our model assumptions and data inputs by performing univariate and bivariate sensitivity analyses. A plausible range was established for each parameter using the highest and lowest values in the published literature or confidence intervals when available, and by adopting alternative assumptions to those used in the base case analysis. When only one data point was available for a given parameter, we established plausible ranges through the use of expert opinion.

Results

Model Calibration

Our final model was well calibrated to outcomes observed in a large European cohort study of pregnant women with HIV infection; we chose to calibrate our model to this study because it was the largest available study conducted in a context where HAART was widely available [33]. Final model parameter sets applied to the self-administered HAART strategy reproduced risks of mother-to-child HIV transmission, reduction in viral load in mothers receiving standard HAART, and risk of both emergency and elective Caesarean section reported in this study (Figure 2). The “no HAART” strategy in the model reproduced rates of vertical transmission consistent with those seen in trials of zidovudine and Cesarean section for prevention of HIV transmission [53], [54].

thumbnail

Figure 2. Model Calibrations.

The model was calibrated to a 2005 European Collaborative Study that examined the effect of HAART on prevention of mother-to-child transmission in over 4000 mother-child pairs [33]. We calibrated the output of our model's self-administered therapy branch to the European study's results for proportion of women receiving an emergency C-section; proportion of women receiving an elective Cesarean section; proportion of women with an undetectable viral load (less than 200 copies/ml); and percent of HIV transmission to the infant.

doi:10.1371/journal.pone.0010154.g002

Effectiveness and Cost-Effectiveness of Directly Observed HAART

The outcomes of five thousand simulated randomized controlled trials of directly observed HAART, compared to self-administered HAART, are presented in Figure 3. While we did include a “no HAART” strategy in our model, this strategy resulted in increased net costs and reduced quality-adjusted life expectancy relative to the self-administered HAART and directly observed HAART strategies in the cohort as a whole, and thus would never be preferred.

thumbnail

Figure 3. Projected Cost-Effectiveness of Directly Observed Highly-Active Antiretroviral Therapy in Pregnancy.

The estimated cost-effectiveness of directly observed highly-active antiretroviral therapy (HAART) as compared to self-administered HAART. Each grey circle represents one of 5000 simulated trials comparing the two strategies, with 200 women in each trial. The incremental cost of directly observed therapy is on the Y-axis, while the incremental change in quality-adjusted life expectancy among infants is on the X-axis. Under base-case assumptions, directly observed therapy reduced costs and increased quality-adjusted life expectancy in most trials.

doi:10.1371/journal.pone.0010154.g003

A reduction in the probability of mother-to-child HIV transmission was seen with directly observed HAART in most trials, with a projected average relative risk of HIV infection of 0.39 among infants born to women receiving DOT versus those receiving self-administered HAART, and a relative risk of 0.09 as compared to women receiving no HAART (Table 2). The reduction in viral load among women receiving directly observed HAART also decreased the requirement for elective Caesarean section among women giving birth at term. There was a resultant average increase in the projected quality-adjusted survival of 11 quality adjusted life-days among infants born to women receiving directly observed antiretrovirals.

thumbnail

Table 2. Projected Average Cost and Effectiveness of Directly Observed HAART in 5000 Simulated Randomized Trials.

doi:10.1371/journal.pone.0010154.t002

On average, direct observation of HAART in the third trimester was projected to be a highly cost-effective intervention, with gains in quality-adjusted survival described above accompanied by net societal costs of $14,233. When trials were stratified according to participants' baseline viral loads, directly observed HAART was projected to be a cost-saving intervention in cohorts with viral loads above 1000 copies/ml. We projected savings of $54,278 per QALY in individuals with viral loads between 1,000 and 10,000 copies/ml, and savings of $26,240 per QALY in individuals with viral loads >10,000 copies/ml (Table 3).

thumbnail

Table 3. Projected Average Cost and Effectiveness of Directly Observed HAART in 5000 Simulated Randomized Trials.

doi:10.1371/journal.pone.0010154.t003

Sensitivity Analyses

We performed wide-ranging sensitivity analyses by varying parameter values and using alternate model assumptions (Table 4). The projected attractiveness of directly observed therapy was insensitive to plausible changes in most model variables, including the probabilities of vertical HIV transmission, prematurity, and emergency and elective Caesarean section; obstetrical costs; and future costs associated with HIV infection and prematurity. Projections were somewhat sensitive to the baseline effectiveness of HAART in pregnant women (i.e. drug effectiveness without directly observed therapy), and the effectiveness of directly observed therapy. Projections were highly sensitive to the enhancement of toxicity of HAART as a result of greater drug exposure with directly observed therapy.

thumbnail

Table 4. Selected Univariate Sensitivity Analyses of Directly Observed HAART Relative to Self-Administered HAART.

doi:10.1371/journal.pone.0010154.t004

In our base case analysis, we assumed that the costs of direct observation of HAART would be due to personnel time required to deliver and observe administration of medications. However, creation of a novel program could be associated with other fixed and capital costs (office space and supplies, acquisition of vehicles, etc.). The results of two-way sensitivity analyses on the effectiveness and cost of directly observed HAART in pregnancy are presented in Figure 4. When we biased our analysis against directly observed therapy by increasing the cost of drug delivery four-fold, and by reducing the effectiveness of direct observation to a 0.5 log change in viral load, the cost-effectiveness ratio associated with this strategy was $313,000 per QALY, a ratio that exceeds a commonly cited threshold for cost-effectiveness [49]. However, this is an extremely unfavourable assumption [50], [55]. Most other combinations of DOT effectiveness and cost were cost-effective or cost-saving, relative to self-administered HAART.

thumbnail

Figure 4. Two-Way Sensitivity Analysis on Effectiveness and Cost of Directly Observed Therapy.

Each diagonal curve represents a different estimate of effectiveness (log10 reduction in viral load) of directly observed therapy: −0.5 log10 (thick line, squared); −0.8 log10 (thin solid line, diamonds); or −1.5 log10 (dashed line, triangles). Incremental cost-effectiveness of directly observed therapy relative to self-administered antiretrovirals appears on the Y-axis. At each level of effectiveness, increasing the cost of directly observed therapy increases the cost-effectiveness ratio associated with this intervention; however, only under the most unfavorable cost and effectiveness assumptions does this ratio exceed $50,000 per quality-adjusted life-year (QALY) gained, a commonly cited cost-effectiveness threshold (horizontal dashed line). Values falling below the X-axis indicate that directly observed therapy is cost-saving.

doi:10.1371/journal.pone.0010154.g004

We postulated that concern for a developing infant might result in enhanced adherence to self-administered HAART by pregnant women with HIV infection. We simulated such an effect by increasing the likelihood that pregnant women taking HAART would have a full (i.e., 2 log10) decrease in viral load with self-administered HAART (Figure 5). As baseline antiretroviral effectiveness of self-administered HAART improved, directly observed administration became less economically attractive at all tested willingness-to-pay (WTP) thresholds. The incremental cost-effectiveness ratio of DOT was cost-effective (under $50,000, a commonly cited cost-effectiveness threshold) as long as the proportion of women responding fully to self-administered HAART was under 0.6.

thumbnail

Figure 5. Sensitivity Analysis of Increasing Baseline Effectiveness of Self-Administered Antiretroviral Therapy.

The proportion of women with a full response to self-administered antiretroviral therapy (i.e., 2.0 log10 reduction in viral load) is presented on the X-axis. The left-sided Y-axis indicates the proportion of 200-person clinical trials that find directly observed therapy to be cost-effective for various willingness-to-pay thresholds (thick black curve, WTP = $0; medium black curve, WTP = $50,000; thin black curve, WTP = $150,000). Average incremental cost-effectiveness ratios for directly observed therapy, relative to self-administered antiretroviral therapy (dark dashed curve) are presented on the right-sided Y-axis; values below $0 indicate that directly observed therapy is a cost-saving health intervention. As the proportion of women who have a full response to self-administered HAART increases, there is a decrease in the proportion of women for whom DOT is cost-effective. An increase in the willingness-to-pay threshold leads to an increase in the proportion of women who find this intervention cost effective. Arrows indicate base-case values.

doi:10.1371/journal.pone.0010154.g005

Discussion

Mother-to-child HIV transmission remains an important but potentially preventable consequence of HIV infection in reproductive-age women. Although improvements in obstetrical management of HIV-infected women have greatly reduced the incidence of perinatal HIV infection, women now comprise 25% of those with newly diagnosed HIV infection and over 146,000 female adults and adolescents currently live with HIV/AIDS in the United States, suggesting that the pool of infants at risk for perinatal HIV infection remains large [1].

Based on the direct relationship between maternal viral load and risk of vertical transmission, and the potential impact of directly observed therapy on viral load, we hypothesized that the provision of directly observed antiretroviral therapy to pregnant women with HIV infection could result in substantial health and economic gains, including a diminished need for Caesarean sections, decreased mother-to-child transmission of HIV, and increased quality-adjusted life expectancy in infants born to HIV-infected women. By diverting the large downstream medical costs associated with pediatric HIV infection, the direct observation of HAART in the third trimester of pregnancy was projected to be a highly cost-effective health intervention from a societal perspective, notwithstanding the short-term costs associated with drug delivery and directly observed drug administration, and targeting DOT to women with viral loads >1000 copies/ml on self-administered HAART was projected to be cost-saving. It is notable that cost-saving health interventions (such as vaccination against diseases of childhood) are uncommon in healthcare; most currently utilized healthcare interventions increase total costs, but are considered cost-effective if they provide a corresponding increase in health [50], [55]. As the Commission on Macroeconomics and Health of the World Health Organization has suggested that interventions can be considered cost-effective if they provide life years at a cost of <3 times per capita gross national income (formerly gross domestic product), our analysis suggests that DOT-CART would be cost-effective not only in high-income countries, but in a large number of middle-income countries as well [49], [56].

While our analysis would strongly support the use of directly observed HAART in women in the third trimester of pregnancy, we may have underestimated the potential health benefits of this intervention. Direct observation of HAART could enhance the health of infants who acquire HIV infection by reducing the probability of primary infection with resistant virus [57], and could also improve future health in the mother by preserving the potency of antiretroviral classes for future use [6]. DOT might be given to those women with particularly unsettled social situations who would be most unlikely to benefit from self-administered HAART, such as those who are homeless, have substance abuse issues, or mental illness. Furthermore, the establishment of structured contact between pregnant, HIV-infected women and public health personnel, as would occur in the context of directly observed antiretroviral therapy, has been associated with improved pregnancy outcomes [58]. Such contacts could link infected women to improved healthcare after delivery as well as introduce them to more healthful behaviours while pregnant and perhaps more open to behaviour change.

It is notable that the favourable health and economic projections associated with directly observed HAART in pregnancy remained robust even in the face of extreme variation in cost and effectiveness of directly observed therapy. We were able to identify only one scenario in which direct observation of HAART in pregnancy would not be preferred to self-administered HAART: a situation in which over 60% of pregnant women responded maximally to self-administered HAART, one that is inconsistent with empiric data on the high-risk women who are the focus of this analysis [14].

Like any mathematical model, the model we present here is a simplified representation of complicated systems, and is thus subject to limitations. In particular, a relatively simple model is limited in its ability to capture the all the complexities related to the clinical management of HIV in pregnancy; thus, models such as this one are not a substitute for randomized clinical trials. However, by synthesizing the best available data on antiretroviral use in pregnancy and the potential benefits of directly observed antiretroviral therapy, modeling can help to inform clinical practice while such trials are pending. Also, by demonstrating the large potential benefits of a novel approach to therapy, such modeling may help to mobilize interest in, and support for, such trials. Our model is particularly important given that this topic is so difficult to study prospectively, due to the small number of HIV-infected infants born in the U.S. Multi-centre clinical trials are an important tool for better defining maximally effective and cost-effective interventions for prevention of vertical HIV transmission, especially with mothers at risk of medication non-adherence.

In summary, based on best available data, we projected that pregnancy provides a unique indication for the use of directly observed antiretroviral therapy for HIV infection. In this context, a modest investment of resources would result in substantial health benefit with a net reduction in societal costs as a result of decreased mother-to-child HIV transmission. Randomized controlled trials of directly observed therapy can be advocated as a reasonable next step in optimizing the prepartum care of HIV-infected women.

Author Contributions

Conceived and designed the experiments: SG DNF. Performed the experiments: CJM DNF. Analyzed the data: CJM DNF. Wrote the paper: CJM DNF.

References

  1. 1. Centers for Disease Control and Prevention (2009) HIV/AIDS Surveillance Report 2007. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. Available: http://www.cdc.gov/hiv/topics/surveillan​ce/resources/reports/. Accessed: 2009 May 21.
  2. 2. Ioannidis JP, Abrams EJ, Ammann A, Bulterys M, Goedert JJ, et al. (2001) Perinatal transmission of human immunodeficiency virus type 1 by pregnant women with RNA virus loads <1000 copies/ml. J Infect Dis 183: 539–545.
  3. 3. Ioannidis JP, Contopoulos-Ioannidis DG (1999) Maternal viral load and the risk of perinatal transmission of HIV-1. N Engl J Med 341: 1698–1700.
  4. 4. Mofenson LM, Lambert JS, Stiehm ER, Bethel J, Meyer WA III, et al. (1999) Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated with zidovudine. Pediatric AIDS Clinical Trials Group Study 185 Team. N Engl J Med 341: 385–393.
  5. 5. Garcia PM, Kalish LA, Pitt J, Minkoff H, Quinn TC, et al. (1999) Maternal levels of plasma human immunodeficiency virus type 1 RNA and the risk of perinatal transmission. Women and Infants Transmission Study Group. N Engl J Med 341: 394–402.
  6. 6. Perinatal HIV Guidelines Working Group (2009) Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1 Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States.1–90. Available: http://aidsinfo.nih.gov/ContentFiles/Per​inatalGL.pdf. Accessed: 2009 November 29.
  7. 7. Burdge DR, Money DM, Forbes JC, Walmsley SL, Smaill FM, et al. (2003) Canadian consensus guidelines for the care of HIV-positive pregnant women: putting recommendations into practice. CMAJ 168: 1683–1688.
  8. 8. Dybul M, Fauci AS, Bartlett JG, Kaplan JE, Pau AK (2002) Guidelines for using antiretroviral agents among HIV-infected adults and adolescents. Recommendations of the Panel on Clinical Practices for Treatment of HIV. MMWR Recomm Rep 51: 1–55. Available: http://www.cdc.gov/mmwr/preview/mmwrhtml​/rr5107a1.htm. Accessed: 2009 May 25.
  9. 9. The EACS Euroguidelines Group (2003) European guidelines for the clinical management and treatment of HIV-infected adults in Europe. AIDS 17: Suppl 2S3–26.
  10. 10. Chesney MA, Ickovics J, Hecht FM, Sikipa G, Rabkin J (1999) Adherence: a necessity for successful HIV combination therapy. AIDS 13: Suppl AS271–S278.
  11. 11. Paterson DL, Swindells S, Mohr J, Brester M, Vergis EN, et al. (2000) Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med 133: 21–30.
  12. 12. Stone VE, Hogan JW, Schuman P, Rompalo AM, Howard AA, et al. (2001) Antiretroviral regimen complexity, self-reported adherence, and HIV patients' understanding of their regimens: survey of women in the HER study. J Acquir Immune Defic Syndr 28: 124–131.
  13. 13. Sethi AK, Celentano DD, Gange SJ, Moore RD, Gallant JE (2003) Association between adherence to antiretroviral therapy and human immunodeficiency virus drug resistance. Clin Infect Dis 37: 1112–1118.
  14. 14. Laine C, Newschaffer CJ, Zhang D, Cosler L, Hauck WW, et al. (2000) Adherence to antiretroviral therapy by pregnant women infected with human immunodeficiency virus: a pharmacy claims-based analysis. Obstet Gynecol 95: 167–173.
  15. 15. Turner BJ, Newschaffer CJ, Zhang D, Cosler L, Hauck WW (2000) Antiretroviral use and pharmacy-based measurement of adherence in postpartum HIV-infected women. Med Care 38: 911–925.
  16. 16. Abaasa A, Todd J, Ekoru K, Kalyango J, Levin J, et al. (2008) Good adherence to HAART and improved survival in a community HIV/AIDS treatment and care programme: the experience of The AIDS Support Organization (TASO), Kampala, Uganda. BMC Health Services Research 8: 241.
  17. 17. Mellins CA, Chu C, Malee K, Allison S, Smith R, et al. (2008) Adherence to antiretroviral treatment among pregnant and postpartum HIV-infected women. AIDS Care 20: 958–968.
  18. 18. Lucas GM, Flexner CW, Moore RD (2002) Directly administered antiretroviral therapy in the treatment of HIV infection: benefit or burden? AIDS Patient Care STDS 16: 527–535.
  19. 19. Mitty JA, Stone VE, Sands M, Macalino G, Flanigan T (2002) Directly observed therapy for the treatment of people with human immunodeficiency virus infection: a work in progress. Clin Infect Dis 34: 984–990.
  20. 20. Macalino GE, Hogan JW, Mitty JA, Bazerman LB, DeLong AK, et al. (2007) A randomized clinical trial of community-based directly observed therapy as an adherence intervention for HAART among substance users. AIDS 21: 1473–1477.
  21. 21. Maru DS-R, Bruce RD, Walton M, Springer SA, Altice FL (2009) Persistence of virological benefits following directly administered antiretroviral therapy among drug users: results from a randomized controlled trial. J Acquir Immune Defic Syndr 50: 176–181.
  22. 22. Wohl A, Garland W, Valencia R, Squires K, Witt M, et al. (2006) A randomized trial of directly administered antiretroviral therapy and adherence case management intervention. Clin Infect Dis 42: 1619–1627.
  23. 23. Lanzafame M, Trevenzoli M, Cattelan AM, Rovere P, Parrinello A (2000) Directly observed therapy in HIV therapy: A realistic perspective? J Acquir Immune Defic Syndr 25: 200–201.
  24. 24. Kirkland LR, Fischl MA, Tashima KT, Paar D, Gensler T, et al. (2002) Response to lamivudine-zidovudine plus abacavir twice daily in antiretroviral-naive, incarcerated patients with HIV infection taking directly observed treatment. Clin Infect Dis 34: 511–518.
  25. 25. Khanlou H, Kandula VR, Yeh V, Stein TG, Sanchez S, et al. (2003) Pilot study of directly observed therapy in highly nonadherent HIV-infected patients in an urban community-based institution. J Acquir Immune Defic Syndr 33: 651–653.
  26. 26. White BL, Wohl DA, Hays RD, Golin CE, Liu H, et al. (2006) A pilot study of health beliefs and attitudes concerning measures of antiretroviral adherence among prisoners receiving directly observed antiretroviral therapy. AIDS Patient Care STDS 20: 408–417.
  27. 27. Dabis F, Newell ML, Fowler MG, Read JS (2004) Prevention of HIV transmission through breast-feeding: strengthening the research agenda. J Acquir Immune Defic Syndr 35: 167–168.
  28. 28. John-Stewart G, Mbori-Ngacha D, Ekpini R, Janoff EN, Nkengasong J, et al. (2004) Breast-feeding and Transmission of HIV-1. J Acquir Immune Defic Syndr 35: 196–202.
  29. 29. Deeks SG, Kitchen CM, Liu L, Guo H, Gascon R, et al. (2004) Immune activation set-point during early HIV infection predicts subsequent CD4+ T cell changes independent of viral load. Blood 104: 942–947.
  30. 30. Mellors JW, Rinaldo CR Jr, Gupta P, White RM, Todd JA, et al. (1996) Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 272: 1167–1170.
  31. 31. Farzadegan H, Hoover DR, Astemborski J, Lyles CM, Margolick JB, et al. (1998) Sex differences in HIV-1 viral load and progression to AIDS. Lancet 352: 1510–1514.
  32. 32. DeHovitz JA, Kovacs A, Feldman JG, Anastos K, Young M, et al. (2000) The relationship between virus load response to highly active antiretroviral therapy and change in CD4 cell counts: A report from the Women's Interagency HIV Study. J Infect Dis 182: 1527–1530.
  33. 33. European Collaborative Study (2005) Mother-to-child transmission of HIV infection in the era of highly active antiretroviral therapy. Clin Infect Dis 40: 458–465.
  34. 34. Schackman BR, Goldie SJ, Freedberg KA, Losina E, Brazier J, et al. (2002) Comparison of health state utilities using community and patient preference weights derived from a survey of patients with HIV/AIDS. Med Decis Making 22: 27–38.
  35. 35. Sanchez JM, Ramos Amador JT, Fernandez de Miguel S, Gonzalez Tomee MI, Rojo Conejo P, et al. (2003) Impact of highly active antiretroviral therapy on the morbidity and mortality in Spanish human immunodeficiency virus-infected children. Pediatr Infect Dis J 22: 863–867.
  36. 36. Egger M, May M, Chene G, Phillips AN, Ledergerber B, et al. (2002) Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet 360: 119–129.
  37. 37. Selik RM, Lindegren ML (2003) Changes in deaths reported with human immunodeficiency virus infection among United States children less than thirteen years old, 1987 through 1999. Pediatr Infect Dis J 22: 635–641.
  38. 38. Mrus JM, Goldie SJ, Weinstein MC, Tsevat J (2000) The cost-effectiveness of elective Cesarean delivery for HIV-infected women with detectable HIV RNA during pregnancy. AIDS 14: 2543–2552.
  39. 39. Mrus JM, Yi MS, Eckman MH, Tsevat J (2002) The impact of expected HIV transmission rates on the effectiveness and cost of ruling out HIV infection in infants. Med Decis Making 22: S38–S44.
  40. 40. Pinkerton SD, Holtgrave DR, Layde PM (2000) Incremental cost-effectiveness of two zidovudine regimens to prevent perinatal HIV transmission in the United States. Prev Med 30: 64–69.
  41. 41. Halpern MT, Read JS, Ganoczy DA, Harris DR (2000) Cost-effectiveness of cesarean section delivery to prevent mother-to-child transmission of HIV-1. AIDS 14: 691–700.
  42. 42. Havens PL, Cuene BE, Holtgrave DR (1997) Lifetime cost of care for children with human immunodeficiency virus infection. Pediatr Infect Dis J 16: 607–610.
  43. 43. Immergluck LC, Cull WL, Schwartz A, Elstein AS (2000) Cost-effectiveness of universal compared with voluntary screening for human immunodeficiency virus among pregnant women in Chicago. Pediatrics 105: E54.
  44. 44. Zaric GS, Bayoumi AM, Brandeau ML, Owens DK (2000) The cost effectiveness of voluntary prenatal and routine newborn HIV screening in the United States. J Acquir Immune Defic Syndr 25: 403–416.
  45. 45. Burman WJ, Dalton CB, Cohn DL, Butler JR, Reves RR (1997) A cost-effectiveness analysis of directly observed therapy vs self-administered therapy for treatment of tuberculosis. Chest 112: 63–70.
  46. 46. Snyder DC, Chin DP (1999) Cost-effectiveness analysis of directly observed therapy for patients with tuberculosis at low risk for treatment default. Am J Respir Crit Care Med 160: 582–586.
  47. 47. Bureau of Labor Statistics (2009) Prices and Living Conditions. U.S. Department of Labor. Available: http://data.bls.gov/data. Accessed: 2009 June 23.
  48. 48. Weinstein MC, Siegel JE, Gold MR, Kamlet MS, Russell LB (1996) Recommendations of the Panel on Cost-effectiveness in Health and Medicine. JAMA 276: 1253–1258.
  49. 49. World Health Organization (WHO) (2009) Choosing Interventions that are Cost Effective (WHO-CHOICE): Cost-effectiveness thresholds. Available: http://www.who.int/choice/costs/CER_thre​sholds/en/index.html. Accessed: 2009 July 21.
  50. 50. Laupacis A, Feeny D, Detsky AS, Tugwell PX (1992) How attractive does a new technology have to be to warrant adoption and utilization? Tentative guidelines for using clinical and economic evaluations. CMAJ 146: 473–481.
  51. 51. Halpern EF, Weinstein MC, Hunink MG, Gazelle GS (2000) Representing both first- and second-order uncertainties by Monte Carlo simulation for groups of patients. Med Decis Making 20: 314–322.
  52. 52. Paltiel AD, Scharfstein JA, Seage GR III, Losina E, Goldie SJ, et al. (1998) A Monte Carlo simulation of advanced HIV disease: application to prevention of CMV infection. Med Decis Making 18: S93–105.
  53. 53. The European Collaborative Study (1994) Caesarean section and risk of vertical transmission of HIV-1 infection. Lancet 343: 1464–1467.
  54. 54. Centers for Disease Control and Prevention (1994) Zidovudine for the prevention of HIV transmission from mother to infant. MMWR Morb Mortal Wkly Rep 43: 285–287.
  55. 55. Tengs TO, Adams ME, Pliskin JS, Safran DG, Siegel JE, et al. (1995) Five-hundred life-saving interventions and their cost-effectiveness. Risk Anal 15: 369–390.
  56. 56. The World Bank (2009) Data & Statistics: Country Groups, Lower Middle-Income Economies. Available: http://go.worldbank.org/D7SN0B8YU0. Date Accessed: August 6, 2009.
  57. 57. De Jose MI, Ramos JT, Alvarez S, Jimenez JL, Munoz-Fernandez MA (2001) Vertical transmission of HIV-1 variants resistant to reverse transcriptase and protease inhibitors. Arch Intern Med 161: 2738–2739.
  58. 58. Turner BJ, Newschaffer CJ, Cocroft J, Fanning TR, Marcus S, et al. (2000) Improved birth outcomes among HIV-infected women with enhanced Medicaid prenatal care. Am J Public Health 90: 85–91.
  59. 59. The European Mode of Delivery Collaboration (1999) Elective caesarean-section versus vaginal delivery in prevention of vertical HIV-1 transmission: a randomised clinical trial. Lancet 353: 1035–1039.
  60. 60. Centers for Disease Control and Prevention (2009) VitalStats. National Center for Health Statistics. Available: http://www.cdc.gov/nchs/VitalStats.htm. Accessed: 2009 June 3.
  61. 61. Holmgren PA, Hogberg U (2001) The very preterm infant - a population-based study. Acta Obstet Gynecol Scand 80: 525–531.
  62. 62. Lipshultz SE, Easley KA, Orav EJ, Kaplan S, Starc TJ, et al. (2002) Cardiovascular status of infants and children of women infected with HIV-1 (P(2)C(2) HIV): a cohort study. Lancet 360: 368–373.
  63. 63. Blanche S, Tardieu M, Rustin P, Slama A, Barret B, et al. (1999) Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet 354: 1084–1089.
  64. 64. Barret B, Tardieu M, Rustin P, Lacroix C, Chabrol B, et al. (2003) Persistent mitochondrial dysfunction in HIV-1-exposed but uninfected infants: clinical screening in a large prospective cohort. AIDS 17: 1769–1785.
  65. 65. The Perinatal Safety Review Working Group (2000) Nucleoside exposure in the children of HIV-infected women receiving antiretroviral drugs: absence of clear evidence for mitochondrial disease in children who died before 5 years of age in five United States cohorts. J Acquir Immune Defic Syndr 25: 261–268.
  66. 66. The International Perinatal HIV Group (1999) The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1: a meta-analysis of 15 prospective cohort studies. N Engl J Med 340: 977–987.
  67. 67. Tuomala RE, Shapiro DE, Mofenson LM, Bryson Y, Culnane M, et al. (2002) Antiretroviral therapy during pregnancy and the risk of an adverse outcome. N Engl J Med 346: 1863–1870.
  68. 68. de Kleine MJ, den Ouden AL, Kollee LA, Nijhuis-van der Sanden MW, Sondaar M, et al. (2003) Development and evaluation of a follow up assessment of preterm infants at 5 years of age. Arch Dis Child 88: 870–875.
  69. 69. Torrance GW, Feeny DH, Furlong WJ, Barr RD, Zhang Y, et al. (1996) Multiattribute utility function for a comprehensive health status classification system. Health Utilities Index Mark 2. Med Care 34: 702–722.
  70. 70. International Neonatal Network, Scottish Neonatal Consultants, Nurses Collaborative Study Group (2000) Risk adjusted and population based studies of the outcome for high risk infants in Scotland and Australia. Arch Dis Child Fetal Neonatal Ed 82: F118–F123.
  71. 71. Sande M, Moellering R, Gilbert D, Pavia A (2003) Antiretroviral therapy in adults. The Sandford Guide to HIV/AIDS Therapy 2003. Hyde Park, VT: Antimicrobial Therapy, Inc. pp. 18–23.
  72. 72. Cohen H (2003) 2003 Drug Topics Red Book. Montvale: Thompson PDR.
  73. 73. Chen KT, Sell RL, Tuomala RE (2001) Cost-effectiveness of elective cesarean delivery in human immunodeficiency virus-infected women. Obstet Gynecol 97: 161–168.
  74. 74. Zupancic JA, Richardson DK, O'Brien BJ, Eichenwald EC, Weinstein MC (2003) Cost-effectiveness analysis of predischarge monitoring for apnea of prematurity. Pediatrics 111: 146–152.
  75. 75. Gilbert WM, Nesbitt TS, Danielsen B (2003) The cost of prematurity: quantification by gestational age and birth weight. Obstet Gynecol 102: 488–492.
  76. 76. Vollmer B, Roth S, Baudin J, Stewart AL, Neville BG, et al. (2003) Predictors of long-term outcome in very preterm infants: gestational age versus neonatal cranial ultrasound. Pediatrics 112: 1108–1114.
  77. 77. Ades AE, Ratcliffe J, Gibb DM, Sculpher MJ (2000) Economic issues in the prevention of vertical transmission of HIV. Pharmacoeconomics 18: 9–22.
  78. 78. Fryback DG, Dasbach EJ, Klein R, Klein BE, Dorn N, et al. (1993) The Beaver Dam Health Outcomes Study: initial catalog of health-state quality factors. Med Decis Making 13: 89–102.
  79. 79. The CASCADE Collaboration (2000) Survival after introduction of HAART in people with known duration of HIV-1 infection. Lancet 355: 1158–1159.
  80. 80. Waitzman N, Romano P, Schleffer R (1994) Estimates of the economic costs of birth defects. Inquiry 31: 188–205.