Maclean, Courtney C BA*†; Stringer, Jeffrey S. A MD†‡
More than 90% of people who are infected with HIV live in the developing world.1,2 Sub-Saharan Africa is currently by far the most affected region; in many African settings, up to 30% of women attending prenatal care clinics are infected with HIV. In the absence of intervention, 35-45% of their infants will become infected during gestation, delivery, or breast-feeding (BF).3 In 1999, the results of the joint US-Ugandan HIVNET 012 clinical trial offered a feasible antiretroviral regimen to prevent peripartum HIV transmission in developing countries. The HIVNET 012 regimen consists of a single oral dose of nevirapine (NVP) given to the mother at the onset of labor and a single dose given to the fetus within 72 hours of birth. Compared to a very short course of zidovudine (widely interpreted to be essentially equivalent to placebo), the HIVNET 012 NVP regimen reduced mother-to-child transmission by 47% at 14-16 weeks of life and 41% at 18 months4 and decreased the overall rate of transmission during gestation and delivery from 25 to 13%.5 Based on these results, the HIVNET 012 NVP regimen is a common method for the prevention of maternal-to-child (MTCT) HIV transmission in the developing world. Its nonprescription price is <$6 per mother-infant pair, and it has been donated to qualified developing world programs by the manufacturer.6
Unfortunately, one-third to one-half of overall vertical HIV transmission occurs during BF, drastically undermining the protective effect of peripartum antiretroviral prophylaxis in areas with high rates of BF. The population effect of this phenomenon is an approximate doubling of MTCT rates in populations where BF is standard practice compared with areas where BF is infrequent.3,7-9 In much of sub-Saharan Africa, the proportion of women who breast-feed approaches 100%.10-13 In many developing world settings, a common option offered to lactating women who are known to be HIV-1 infected is to breast-feed exclusively for 6 months, followed by early, abrupt cessation. Formula feeding is not often advocated because of concerns that early breast milk avoidance in resource-poor settings would be accompanied by an increase in infant mortality that might offset any gains achieved by decreasing HIV-1 transmission.
Preventing MTCT during BF is the focus of significant research effort, and studies in numerous sites across Africa (Botswana, Ethiopia, Kenya, Malawi, Rwanda, South Africa, and Uganda) are evaluating the efficacy of postpartum antiretrovirals in preventing transmission during lactation. Antiretrovirals under study include various regimens of zidovudine, NVP, lamivudine (3TC), or a combination of these. Courses vary from 1 week to 6 months, and the regimens are given to the mother, the infant, or both. Currently, data from antiretroviral trials are limited to preliminary results from the Stopping Infection from Mother-to-Child Breast-feeding in Africa (SIMBA) phase III trial.14 The SIMBA trial treated 413 pregnant women in Uganda and Rwanda with zidovudine and didanosine during gestation, delivery, and 1 week postpartum. Infants were randomly assigned to receive 3TC or NVP during BF and followed for 6 months. SIMBA researchers found that the efficacies of NVP and 3TC were not significantly different, and the overall postnatal transmission rates in each arm were <2%.
Postpartum antiretroviral regimens, if proven efficacious, could decisively advance our ability to decrease MTCT in resource-poor settings. However, the current cost of some antiretroviral regimens presents a challenge to the limited health care resources of most countries in sub-Saharan Africa. The objective of this analysis was to determine the circumstances under which some of the antiretroviral interventions currently under study might be cost-effective in resource-limited settings.
A Markov model was used to assess the circumstances under which the following infant feeding strategies-currently of unknown efficacy, but the subject of ongoing clinical trials-might be cost-effective: BF for 6 months with daily infant NVP prophylaxis; maternal 3-drug combination antiretroviral therapy (ART) during pregnancy and for 6 months of BF; and maternal 3-drug combination ART only for women with CD4+ count ≤200 cells/mL. Markov models try to replicate the natural history of disease by simulating transitions between disease states. In this model, infants were assumed to progress through the following states: uninfected, HIV-infected, AIDS, and dead. Antiretroviral interventions were compared to currently practiced feeding strategies of BF for 12 months; BF for 6 months; and formula feeding for 12 months. All strategies other than the 3rd included women with any CD4+ count. Strategies were evaluated in the context of available voluntary counseling and testing (VCT) and intrapartum and neonatal single-dose NVP prophylaxis.
The hypothetical cohort consisted of 40,000 pregnant women presenting for antenatal care in Lusaka, Zambia. All women were offered VCT; those who tested positive were offered the intervention. The model was designed from the perspective of the public health care payer. Clinical and cost estimates were derived from the literature and regional sources, and sensitivity analyses were performed on uncertain estimates. Costs were expressed in year 2003 US dollars and effectiveness in quality-adjusted life-years (QALYs). QALYs are the years of life saved by an intervention, weighted using utility estimates to reflect the quality of life. Future costs and effects were discounted at a rate of 5% per year.15 Strategies were evaluated using incremental cost-effectiveness ratios (ie, the additional cost per additional unit of health gained). By World Bank measures, decision makers in very low-income countries would be willing to pay $64 per QALY gained ($50 per QALY gained, adjusted to 2003 dollars).16 By this criterion, the economically preferred strategy is the most effective intervention that costs ≤$64 per QALY.
Reported seroprevalence among pregnant women in sub-Saharan Africa (Table 1) varies from 0.5% in Senegal to 45% in Botswana.1 We used a base case prevalence of 15%, with sensitivity analyses from 0.5-45%.
Outcomes in life-years were quality adjusted using a utility estimate of 0.877 for infants who were HIV-infected and 0.495 for those with AIDS, where 1 represents perfect health and 0 represents death.17
Consent to Testing
A recent study conducted in Lusaka, Zambia found that of 830 women offered HIV testing at antenatal care, 64% accepted.18 Sensitivity analyses ranged from 30-100%.
The same study from Lusaka reported that 25 of 98 HIV-infected women (26%) who were provided NVP for MTCT prophylaxis were nonadherent (ie, did not ingest the NVP tablet), as assessed by liquid chromatographic assay for NVP in cord blood. Adherence to peripartum NVP varied between 50-100% in sensitivity analyses. The base case estimate of nonadherence to ART during BF was 26%; it varied from 0-100% in sensitivity analyses due to additional uncertainty.
Proportion of Stillbirths
A 4-year retrospective study at a district hospital in Rwanda found that 3408 deliveries produced 3497 neonates, 349 (10%) of whom were stillbirths.19 We adopted this value as our base case estimate.
Toxicity of Nevirapine
The HIVNET 012 clinical trial recorded 2 serious adverse events that were “possibly, but unlikely to be, related to” NVP: transient respiratory distress at birth in an infant with meconium staining, and a nonmacerated stillbirth to a woman who had taken NVP 3.5 hours before delivery. There are as yet no published data on the toxicity of NVP given daily to infants during BF. Preliminary analysis of HIVNET 023, a phase I trial of infant NVP during BF,20 revealed no serious adverse events related to NVP. Preliminary results from the SIMBA trial reported 8 deaths (4%) among the 198 infants in the NVP arm.14 However, the investigators did not consider them to be related to the study drug. Our model assumed a baseline monthly toxicity risk of zero, but sensitivity analyses evaluated toxicity-related death rates ranging from 0.1-10%.
In Utero and Intrapartum HIV-1 Transmission Risk
In the HIVNET 012 trial,5 the risk of maternal-to-child transmission among the 313 infants assigned to the zidovudine arm (widely assumed to be equivalent to placebo) was 25% at 14-16 weeks of life, and NVP therapy reduced this risk to 13% (relative efficacy = 47%). The efficacy of NVP was varied within the trial's 95% confidence limits (20-64% relative reduction) in sensitivity analyses. The model accounted for higher transmission risk among women with CD4+ lymphocyte counts <200 cells/mL. Subanalyses from the zidovudine-treated group in the same study21 reported an 18-month transmission rate of 59% in mothers with CD4+ lymphocyte counts <200 cells/mL and 19.8% in mothers with CD4+ ≥200. In the same subanalysis, the efficacy of NVP in reducing MTCT in mothers with CD4+ counts ≥200 was 34.8%. Therefore, the risk of MTCT among infants of mothers with CD4+ counts ≥200 who receive NVP prophylaxis is 12.9% (0.198 (1-0.348)).
In the absence of data from developing world settings, the efficacy of combination ART in decreasing MTCT was based on a prospective cohort study conducted in the United States,22 which found an efficacy of 82% among mothers who took combination ART for at least 1 trimester during pregnancy compared to those who had no therapy. Rates were varied between the reported 95% CIs of 65-100% in sensitivity analyses. The PACTG 316 randomized trial is the only study that has reported the efficacy of combination ART based on specific CD4+ count strata. They analyzed the efficacy of single-dose maternal-infant NVP when administered in addition to standard ART at sites in the United States, Europe, Brazil, and the Bahamas. The reported efficacy of combination ART alone was 91% among mothers with CD4+ counts <200 cells/mL.23 We chose not to use this estimate for the efficacy of combination ART among women of all CD4+ counts because it was deemed to be inappropriately high for resource-limited settings.
Breast-feeding HIV-1 Transmission Risk
A clinical trial in Nairobi randomly assigned 425 HIV-infected women to either BF or formula feeding and followed the mother-infant pairs for a median of 2 years.24 After adjusting for infection acquired during pregnancy, the interval rates of HIV infection among infants of mothers assigned to the BF arm of the Nairobi clinical trial were: 0, 6.6, 4.6, 3.5, 4.3, and 4.4% at birth, 6 weeks, 14 weeks, and 6, 12, and 24 months, respectively. Corresponding rates for formula-fed infants were 0, 6.6, 3.5, 2.7, 2.3, and 2.3% (transmission continues to occur, presumably due to noncompliance). The 0- to 6-week interval rate was adjusted for infection acquired during pregnancy by subtracting the 0- to 6-week interval rate during BF minus that during formula feeding from the baseline BF interval rate. Sensitivity analyses ranged from 1 to many multiples of these baseline estimates.
To date there are no published data on the efficacy of combination ART in preventing HIV transmission during BF, although trials are ongoing. The efficacy of maternal combination ART during BF was assumed to be equivalent to that observed during pregnancy and delivery: 82% relative reduction on average, and 91% in women with CD4+ <200 cells/mL. Relative reductions from 50-100% were examined in sensitivity analyses.
Based on preliminary results from the SIMBA trial,14 the prophylactic efficacy of daily infant NVP during BF was calculated to be 37% (expected transmission rate of 5.9% at 6 months of age based on data from HIVNET012,5 observed rate of 3.7% in SIMBA = 37% relative reduction). Sensitivity analyses ran between 0-100%.
Natural History of Pediatric HIV Infection
A 5-year prospective study in Rwanda25 found that the cumulative probabilities of death in 54 HIV-infected children at 1, 2, and 5 years of age, respectively, were 0.26, 0.45, and 0.62. The cumulative probabilities of developing AIDS at the same ages were 0.17, 0.28, and 0.35. The median duration of survival after the occurrence of AIDS was 9 months, with a range of 4-21 months. These rates were incorporated as transitional probabilities in the Markov model.
Mortality Due to Not Breast-feeding
The Nairobi trial24 found no increased risk of mortality with formula feeding; however, all of the participants had access to clean water and free formula and were extensively and repeatedly educated on the proper preparation of formula. In most settings in sub-Saharan Africa, these criteria could not be met. As one author notes, “Although it has been shown that it is possible to withhold BF and reduce HIV transmission without increasing infant mortality in a highly selected population of HIV-infected women in a low-income country, these results cannot be generalized to most of the developing world.”26
A World Health Organization meta-analysis of all available data from 1980-1998 on mortality attributable to avoidance of BF included studies from Brazil, the Gambia, Ghana, Pakistan, the Philippines, and Senegal.13 However, none of the African studies could be included in their pooled analysis of mortality among nonbreast-fed infants because virtually all babies in those studies were breast-fed well into the 2nd year of life. Therefore, model estimates were based on the Pakistan data, which had the highest mortality rates reported. The cohort study of 2166 infants in rural areas and urban slums in Pakistan found that the mortality of nonbreast-fed infants compared to breast-fed infants reached an odds ratio of 21.3 during the 1st month of life, corresponding to an increased risk of death of 0.78%. Mortality due to not breast-feeding decreased to a low of 0.09% by 16 months of age (odds ratio 4.5).
HIV Counseling and Testing and CD4 Testing
Previous estimates of the cost of prenatal VCT (Table 1) have ranged from $4.0015 to $7.30.27 We used estimates from our large prevention of MTCT program in Lusaka, where it costs $6.92 per patient counseled (not including start-up or testing costs),28 $1.99 to test an HIV-negative woman, and $4.79 to test an HIV-positive woman. The cost of testing was varied from $1.50-$5.00 for a negative woman, and $4.50-$8.00 for a positive woman. CD4+ testing in Lusaka costs $30.00 (includes assays, technician time, quality control procedures); sensitivity analyses ranged between $10-$40.
Nevirapine and HAART
The estimated cost of NVP was $5.12 for a 200-mg maternal dose and $0.20 for 7 mg of infant syrup, based on the published average wholesale price.29 These prices reflect drug acquisition only; they do not account for distribution, waste, spoilage, or discounts that may be available to developing world purchasers. Total costs between $0.15 (the estimated cost of dispensing donated drug) and $8.00 per dose were explored in sensitivity analyses. Based on experience in Zambia, the estimated price of combination ART was $44.44 per month, and costs between $0.15-$50.00 were evaluated.
Lifetime Cost of Perinatal HIV Treatment
The lifetime cost of health care for an HIV-infected child was based on calculations by Marseille et al15 and estimated at $321 after adjustment to year 2003 US dollars. This estimate was varied from 0-$600 in sensitivity analyses.
Based on average consumption from an ongoing MTCT prevention program in Lusaka, we estimated that formula for infants aged 0-3 months cost $18.95 per month, $32.06 for ages 4-6 months, and $13.60 for ages 7-12 months. Costs of zero to 1 times the base case were examined.
The cost-effectiveness results for infant NVP prophylaxis are reported in Table 2; maternal combination ART strategies are reported in Tables 3 and 4. Using base case estimates, neither maternal combination ART nor infant NVP prophylaxis was economically preferred. BF for 6 months was the preferred strategy: it cost $806,995 and generated 446,208 QALYs. Providing daily infant NVP generated 1183 additional QALYs but cost an additional $93,638, and its incremental cost-effectiveness ratio (ICER) of $79/QALY exceeded the standard willingness to pay ($64/QALY) for most resource-poor settings. Maternal combination ART strategies were potentially very effective: compared to BF for 6 months without postpartum antiretrovirals, providing maternal combination ART based on CD4 count generated 661 additional QALYs, and maternal combination ART to all HIV-infected mothers generated 5042 additional QALYs. However, neither strategy was economically preferred in the base case because of ART cost: their ICERs ($317/QALY and $87/QALY, respectively) were too costly for most resource-limited settings. Under our base case assumptions, providing maternal ART to women with CD4+ ≤200 cells/mL was less effective and more costly than providing daily infant NVP during 6 months of BF. The remaining strategies-BF for 12 months and formula feeding-were less effective and more costly than the other strategies. Formula feeding was less effective than other strategies because infants in that strategy incur an increased risk of non-HIV infectious mortality and continue to be at risk for HIV transmission (albeit at a much lower rate) due to noncompliance; thus, it would not be preferred even if the cost of formula were reduced substantially.
Sensitivity analyses demonstrated that in order for BF with daily infant NVP to be economically preferred, it would have to be at least 44% effective, compared to the 37% effectiveness used in the base case analysis, or cost ≤$5 per month, compared to the $6 base case cost. Additionally, NVP would be economically preferred if adherence were ≥87% or the cost of caring for an infected infant exceeded $575. The cost-effectiveness results were not sensitive to variation in other estimates. Under circumstances in which NVP was donated (and systems had to fund $0.15 per monthly dose for distribution), NVP would only have to be minimally effective (<1%) to be the preferred strategy. Assuming a toxicity rate of 0%, supplying donated NVP would be slightly more effective than BF for 6 months without a postpartum antiretroviral intervention and would be less expensive (by preventing even a few cases of HIV transmission, it would save the costs of future HIV care for those children). In sensitivity analyses, if the rate of toxicity were 0.1%, donated NVP would have to be 3% effective in order to be preferred. The highest rate of toxicity at which donated NVP could remain preferred was 1.5%.
The results for ART to all known HIV-infected mothers were sensitive only to estimates of adherence and the cost of ART. If adherence exceeded 83%, ART to all mothers would become the preferred strategy under the base case assumption of 82% efficacy. ART would also be preferred if the efficacy exceeded 95% or the cost of ART (including administration and monitoring) were <$34.50 per month. The cost-effectiveness results were not sensitive to variation in other estimates.
Providing maternal combination ART only for women with CD4+ ≤200 cells/mL would be preferred only in the specific circumstances in which the cost of a CD4+ test was very low and the proportion of women having a CD4 ≤200 cells/mL was very low. The results were not sensitive to changes in other variables, including estimates of adherence, efficacy, and cost of combination ART. Combination ART based on CD4+ was not preferred because of the high cost of ART and CD4 testing, and also because it had a much lower efficacy compared to ART to all known HIV-infected mothers (compared to ART based on CD4+, ART to all known HIV-infected mothers generated 4381 more QALYs at an additional cost of 227,791, for an ICER of $52/QALY). When the cost of CD4 testing was set to zero in sensitivity analyses, combination ART based on CD4 testing became the preferred strategy when the cost of ART was ≤$22; however, as discussed above, ART to all known HIV-infected mothers becomes cost-effective (has an ICER ≤$64/QALY) if ART costs ≤$34.50 per month. Thus, in situations in which ART based on CD4 might have been preferred, it is dominated by ART to all mothers.
In many developing world settings, lactating women who are known to be HIV-1-infected are encouraged to BF exclusively for 6 months, followed by early, abrupt cessation. The results of our analysis suggest that such a policy remains the economically preferred strategy. However, postpartum antiretroviral regimens, if proven efficacious, could decisively advance our ability to decrease MTCT, and our results demonstrate that under some circumstances they could represent an economically sound public health strategy, even in settings of extreme resource limitations.
Infant Nevirapine Prophylaxis
Definitive statements regarding the cost-effectiveness of NVP during BF must await the final results of ongoing BF HIV prevention trials. The conclusions of the SIMBA trial remain under debate because the trial lacked a control group and results must be compared to historical controls. The most appropriate historical comparison is the HIVNET 012 trial; however, the SIMBA trial differed in several key areas: Mothers in the SIMBA trial received zidovudine and didanosine starting at 36 weeks, during delivery, and for 1 week postpartum-a regimen that may decrease maternal viral burden significantly-as opposed to the HIVNET 012 single-dose NVP regimen, which prevents MTCT without affecting maternal viral titers. Maternal HIV RNA levels at delivery were significantly lower in the SIMBA trial vs. the HIVNET 012 trial. The duration of membrane rupture was significantly shorter in the SIMBA trial. Finally, the duration of BF was significantly shorter in the SIMBA trial (a median of 3.3 months vs. 9.5 months in HIVNET 012). Each of these factors is associated with the risk of HIV transmission.
However, even under our conservative base case efficacy estimate of 37%, BF for 6 months with daily infant NVP would be cost-effective if NVP cost <$5.00 per month, just $1.00 less than current market price. If NVP were donated, and countries had to fund a small amount for distribution ($0.15/month), NVP would only have to minimally effective in order for BF for 6 months with NVP to be preferred. Currently, NVP is donated by the manufacturer to be qualified developing country programs for the prevention of peripartum MTCT. If NVP or other antiretrovirals prove effective in preventing MTCT during BF, it remains to be seen whether additional donations could be secured to support the more extended prophylaxis required during BF.
We found that NVP prophylaxis would be economically preferred if the cost of caring for an infected infant exceeded $575 (the estimated average additional public health expenditure for an HIV-infected child was $321). However, this estimate would dramatically increase if government-sponsored antiretroviral therapy for HIV-infected children became widely available. Progress is certainly being made towards that goal, but advancement is slow, and especially in rural areas, many other aspects of general health care and HIV care must be implemented first. Government-sponsored antiretroviral therapy for HIV-infected children would prolong their expected lifespan and increase the public health expenditure. Therefore, estimates of willingness to pay would be increased correspondingly, and NVP prophylaxis or maternal ART likely would be economically preferred in a wider variety of circumstances.
Maternal Combination ART
Providing combination antiretrovirals to all known HIV-infected mothers during pregnancy and 6 months of BF potentially represents the most clinically effective infant feeding strategy, should its effectiveness be proven. Pending the results of ongoing trials, we were required to make assumptions regarding the efficacy of antiretrovirals during BF and patient adherence during extended antiretroviral treatment. However, supplying combination antiretrovirals was also one of the most costly interventions, and providing maternal ART to all known HIV-infected mothers was preferred only if it was donated or available at a reduced price (<$34.50 per month, including the cost of administration and monitoring). The price of combination ART has been decreasing in some areas of Africa and may reach this threshold.
Interestingly, although providing combination ART to mothers with CD4+ count ≤200 cells/mL is a treatment arm in a number of ongoing clinical trials, our analysis suggests that providing combination ART to all known infected mothers may be preferable under certain circumstances. Providing combination ART to all known infected mothers is more costly than limiting it to women with CD4+ ≤200 cells/mL, but much more effective for prevention of MTCT, such that the ICER for ART to all mothers compared to ART based on CD4 is $52/QALY (on par with the standard willingness to pay for resource-poor settings). Thus, in a situation where ART based on CD4 might have been preferred (ie, when the cost of ART is decreased), it is dominated by ART to all mothers.
Providing ART based on CD4 was the preferred strategy only when the cost of a CD4 test was low and the proportion of women having a CD4+ ≤200 cells/mL also was very low. This may appear counterintuitive because if the proportion of women with CD4 ≤200 is low, many more costly CD4 tests are required to identify 1 eligible candidate for ART. However, women who have a CD4 count ≤200 cells/mL have a substantially increased rate of MTCT (0.549 vs. 0.25) and although ART will decrease the rate of transmission considerably, many women will either refuse testing or will not adhere to therapy. Thus, while spending $30 for a CD4 test appears more efficient if a higher proportion of women have a CD4 ≤200, that gain is outweighed by the decreased effectiveness associated with higher transmission and the increased costs incurred by women who do not receive or adhere to the intervention ($321 for the cost of caring for an HIV-infected child).
Uncertainty remains regarding key parameters in the model: the exact rates, risks, and timing of HIV transmission during BF are still not known with monthly precision, and little is known regarding the risk of increased morbidity and mortality associated with not breast-feeding in sub-Saharan Africa. However, sensitivity analyses demonstrated that the recommendations based on the model were robust to both the rate of HIV transmission during BF and the rate of increased mortality among nonbreast-fed infants.
Additionally, this analysis does not incorporate any external benefits derived from 9 months of ART, including improved maternal health, prevention of adult-to-adult transmission, or any decreased costs of orphan care associated with increased maternal longevity. Similarly, it does not address the potential costs to the mother of antiretroviral toxicity or resistance. Such benefits would affect efficacy of maternal ART strategies and may be important to address in future analyses, especially if the cost of combination ART falls and funds for short-term ART for prevention of MTCT become available.
Most importantly, the recommendations of this analysis depend on the availability of VCT and an NVP-based prevention program. In some areas of the developing world, particularly urban settings, such programs have become a reality and the focus is now on the topics discussed in this paper. However, for the vast majority of women living in isolated or rural areas where even basic prevention of MTCT services are not available, the emphasis must remain on establishing such programs.
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