The efficacy of ARVs in the prevention of MTCT of HIV is widely accepted[54
]. Two studies report an association between in utero
ARV exposure and infant neurologic dysfunction possibly related to MT [32
], but the true prevalence and severity of this postulated MT remain controversial [55
]. Motivated by the possibility that the association between ARV exposure and MT is causal [39
], we conducted an exploratory analysis in order to determine the prevalence and severity of MT at which current ARV recommendations for PMTCT would merit change [43
This decision analytic model assesses the 18-month risks for pediatric HIV transmission and neurologic MT, following the administration of six different PMTCT regimens to pregnant, HIV-infected women in sub-Saharan Africa. Model results reflect the published efficacy of ARVs for PMTCT; base case estimates of HIV transmission at 18 months in breastfed infants range from 4.9% with 3-drug ART to 30.4% with no ARVs. These results calibrate with results from observational studies [57
] and with syntheses of PMTCT trials in sub-Saharan Africa [3
], including 40-50% (relative) [59
] and 14-15% (absolute) [59
] increases in MTCT risk due to breastfeeding. Because MT has primarily been attributed to in utero
NRTI exposure, the three least effective PMTCT regimens, all of which exclude antepartum NRTIs, demonstrate low toxicity risks. Overall, 3-drug ART initiated in the first trimester results in many fewer pediatric HIV infections, slightly more cases of pediatric neurologic MT, and substantially fewer total adverse pediatric outcomes (HIV infections and MT cases) than the less toxic but less effective regimens.
Published studies of ARV-associated MT have differed in methodology and MT case definition, which may explain inconsistent findings [2
]. In addition, most studies have not controlled for maternal substance abuse and socioeconomic factors [68
], high maternal viral load [50
], and maternal disease stage [39
], all of which have been hypothesized to cause infant mitochondrial dysfunction and adverse neurologic outcomes [39
]. We therefore chose data from the only two studies using routine neuropsychiatric evaluations of living, HIV-uninfected children [32
]. Brogly et al.
demonstrated a significantly higher risk of MT when NRTIs (ZDV, 3TC, or both) were initiated in the third trimester than in the first trimester [39
]. They postulate a period of neurodevelopment late in gestation in which the fetal brain is uniquely sensitive to NRTI-induced MT [70
]. The authors were unable to control for high maternal RNA at delivery (likely a result of late ARV initiation) and maternal drug use (a potential cause of late ARV initiation, although not associated with MT in this study). Because these factors may have led to the overestimation of MT risk from 3rd
-trimester NRTI initiation, our base case analysis conservatively relied on the MT risk associated with any
ZDV, 3TC, or ZDV/3TC exposure, regardless of timing (1.88% - 2.04%).
Our results demonstrate that at MT prevalences lower
than the base case risks (as in the EPF, range 0.26-0.87%) [32
], 3-drug ART would still minimize total adverse outcomes. More importantly, these results remain true at MT prevalences higher
than the base case scenario. Our “worst-case” MT scenario used data from subgroups with 3rd
-trimester initiation of ZDV, 3TC, or ZDV/3TC in PACTG 219/219C; results suggest that even if these “worst-case” MT estimates were correct, a change in recommended ARVs for PMTCT would be warranted only if the very highest or lowest published HIV risks associated with each regimen were also true. HIV transmission risks at 18 months in the “best-case” and “worst-case” scenarios are well outside commonly reported ranges [1
Currently reported prevalences of MT are therefore unlikely to change PMTCT recommendations. However, little is known about the morbidity and mortality of ARV-associated neurologic MT [32
], and prognostic information must be extrapolated from reports of congenital mitochondrial dysfunction [52
]. As new data specific to ARV-associated MT emerge [4
], a primary factor in the choice of PMTCT regimen will be the relative disability of MT compared to that of pediatric HIV infection. Pediatric HIV disease substantially reduces life expectancy in sub-Saharan Africa, even when therapy is available [77
], and may itself be associated with significant neurodevelopmental delay [81
]. If pediatric HIV infection consistently causes greater morbidity and mortality than MT, then the balance of risk and benefit will always favor more effective regimens for PMTCT. If, however, MT is markedly more disabling than pediatric HIV (for example, if effective therapies for pediatric HIV become widely available), then policy makers may choose PMTCT strategies that permit more cases of HIV infection in order to avoid MT in uninfected children. The combined outcome of HIV infections plus MT cases allowed us to estimate that, at base-case MT risks, neurologic MT will need to be at least 6.4 times more disabling than HIV infection in order to prompt a change in current PMTCT recommendations.
Of note, this model did not examine maternal outcomes. Emerging data suggest a benefit to ART initiation at CD4 > 200/μL, as reflected in recent changes to US treatment guidelines [82
]. Therefore, women included in our model are likely to benefit from 3-drug ART during pregnancy, and the effects on maternal health of withdrawing ART after use for PMTCT remain unknown [44
]. Maternal drug-resistant HIV resulting from single- or dual-drug PMTCT regimens may also result in reduced efficacy of ART when it is eventually initiated [85
]. These maternal effects may tip the balance of risk and benefit in favor of 3-drug ART when both maternal and pediatric outcomes are considered. Additionally, the model did not incorporate the costs of each PMTCT regimen or of clinical care for HIV- or MT-affected children after birth. In settings with severely constrained health care resources, concerns for costs may outweigh concerns for toxicity in the selection of ARV regimens for PMTCT.
This analysis required several simplifying assumptions. First, data are limited on late postpartum transmission rates by actual infant feeding practices [7
]. Second, the model did not account for the neurodevelopmental effects of maternal age, preterm delivery, or stage of maternal HIV disease, which may affect pediatric neurologic outcomes [86
]. Finally, women with CD4 < 200/μL merit 3-drug ART for their own HIV infections as well as for PMTCT[43
], and therefore were intentionally excluded from the model. Because MTCT data were not limited to women with high CD4 counts, the base case analysis likely overestimates transmission risks for women not requiring ART themselves [19
The “best-case” scenario, in which the lowest published HIV transmission risks were attributed to each regimen, may more closely approximate true MTCT risks from women with less advanced disease. The results of the “best case” HIV scenario were unchanged from the base case, except when the highest published MT risks for 3-drug ART were simultaneously considered. For breastfed infants in this “best-case HIV/worst-case MT” scenario, scZDV/sdNVP/CBV was superior to 3-drug ART, due primarily to the high MT risk assigned to 3rd
-trimester 3TC exposure. For formula-fed infants, all ARV regimens were superior to 3-drug ART, due to very low HIV risks assigned to less intensive regimens. The small differences in total adverse outcomes between strategies suggest that further studies are required to investigate 1) whether scZDV regimens are effective among women with CD4 > 200/μL, and 2) whether MT risks with 3-drug ART approach those observed in select subgroups of PACTG 219/219C [39
]. If such data emerge and are simultaneously true, short-course regimens may be appropriate alternatives to 3-drug ART in women with high CD4 counts, especially when formula-feeding is feasible.
In resource-limited settings, concerns for toxicity, as well as for cost, may influence the selection of less effective ARV regimens for PMTCT than are recommended in developed nations [43
]. Currently available data suggest that total pediatric adverse outcomes (HIV infections and cases of neurologic mitochondrial toxicity) are minimized by the use of PI-based 3-drug ART for PMTCT. Less effective ARV regimens would only be substantially superior to 3-drug ART if the very highest or lowest published risks of HIV, as well as the highest published risks of MT, associated with each strategy were simultaneously true, or if ARV-related mitochondrial toxicity were markedly more disabling than pediatric HIV infection. Access to diagnosis, prenatal care, and ARVs for HIV-infected women in resource-limited settings remain crucial to reducing the more than 500,000 perinatal infections that occur worldwide each year, and every effort should be made to provide 3-drug ART to women who require therapy for their own health [54
]. For women with less advanced HIV disease, nucleoside-sparing PMTCT regimens, or regimens that avoid combination nucleosides, may warrant further investigation. In the meantime, currently reported risks of mitochondrial toxicity should not lead providers or patients to avoid the use of 3-drug ART during pregnancy for PMTCT, and efforts should be expanded to increase the availability of 3-drug ART for PMTCT in resource-limited settings.