Home Current Issue Previous Issues Published Ahead-of-Print Collections For Authors Journal Info
Skip Navigation LinksHome > November 12, 2008 - Volume 22 - Issue 17 > Antiretroviral drugs for preventing mother-to-child transmis...
AIDS:
doi: 10.1097/QAD.0b013e3283189bd7
Epidemiology and Social

Antiretroviral drugs for preventing mother-to-child transmission of HIV in sub-Saharan Africa: balancing efficacy and infant toxicity

Ciaranello, Andrea La; Seage, George R IIIe; Freedberg, Kenneth Aa,b,d,f; Weinstein, Milton Cf; Lockman, Shahinc,g; Walensky, Rochelle Pa,b,c,d

Free Access
Article Outline
Collapse Box

Author Information

aDivision of Infectious Disease, USA

bDivision of General Medicine, Department of Medicine, Massachusetts General Hospital, USA

cDivision of Infectious Disease, Brigham and Women's Hospital, USA

dCenter for AIDS Research, Harvard Medical School, USA

eDepartment of Epidemiology, USA

fDepartment of Health Policy and Management, USA

gDepartment of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA.

Received 15 May, 2008

Revised 29 August, 2008

Accepted 5 September, 2008

Correspondence to Andrea L. Ciaranello, MD, Division of Infectious Diseases, Massachusetts General Hospital, 50 Staniford Street, 9th Floor, Boston, MA 02114, USA. Tel: +1 617 724 8445; fax: +1 617 726 2691; e-mail: aciaranello@partners.org

Collapse Box

Abstract

Objective: Antiretroviral drugs can prevent mother-to-child transmission of HIV infection, but in-utero antiretroviral exposure may be associated with neurologic symptoms due to mitochondrial toxicity. We sought to identify the currently recommended regimen to prevent mother-to-child transmission that optimally balances risks of pediatric HIV infection and neurologic mitochondrial toxicity.

Design: Published MTCT and mitochondrial toxicity data were used in a decision analytic model of MTCT among women in sub-Saharan Africa.

Methods: We investigated the HIV and mitochondrial toxicity risks associated with no antiretroviral prophylaxis and five recommended regimens ranging from single-dose nevirapine to three-drug antiretroviral therapy (ART). Sensitivity analyses varied all parameters, including infant feeding strategy and the disability of mitochondrial toxicity relative to HIV.

Results: Provision of no antiretroviral drugs is the least effective and least toxic strategy, with 18-month HIV risk of 30.4% and mitochondrial toxicity risk of 0.2% (breastfed infants). With increasing drug number and duration, HIV risk decreases markedly (to 4.9% with three-drug ART), but mitochondrial toxicity risk also increases (to 2.2%, also with three-drug ART). Despite increased toxicity, three-drug ART minimizes total adverse pediatric outcomes (HIV plus mitochondrial toxicity), unless the highest published risks are true for both HIV and mitochondrial toxicity, or the disability from mitochondrial toxicity exceeds 6.4 times that of HIV infection.

Conclusion: The risk of pediatric mitochondrial toxicity from effective regimens to prevent mother-to-child transmission is at least an order of magnitude lower than the risk of HIV infection associated with less-effective regimens. Concern regarding mitochondrial toxicity should not currently limit the use of three-drug ART to prevent mother-to-child transmission where it is available.

Back to Top | Article Outline

Introduction

The use of antiretroviral drugs to prevent mother-to-child transmission (PMTCT) of HIV infection is one of the most successful achievements in HIV prevention. Following the Pediatric AIDS Clinical Trial Group (PACTG) Study 076 in 1994 [1], zidovudine (ZDV) monotherapy was widely used for PMTCT, where available [2]. Subsequent trials have investigated antepartum, intrapartum, and postpartum regimens combining ZDV, lamivudine (3TC), nevirapine (NVP), and protease inhibitors [3–16]. MTCT rates have been reduced from more than 25% [1,17] to less than 2% [4,8,18] when potent three-drug antiretroviral therapy (ART) is available and breastfeeding is avoided, and recently reported interventions have reduced transmission to breastfed infants from over 40% (at 24 months of age) [3,17] to 1–7% (at 6–18 months) [19–26].

Most regimens have demonstrated favorable safety profiles for both mothers and infants during the duration of trial follow-up [3,8,10,16,27]. In 1999, however, French perinatologists reported eight cases of severe cognitive and neurological dysfunction among HIV-negative children after in-utero antiretroviral exposure [28]. These neurologic symptoms, including hypotonia, seizures, encephalopathy, and neuropathy, were similar to both congenital mitochondrial dysfunction in children and antiretroviral-induced mitochondrial toxicity in HIV-infected children and adults [28]. Since this first report, other studies of the effects of in-utero antiretroviral exposure on mitochondrial function in HIV-negative children have differed in methodologies and conclusions [29–41].

Clinicians and policy makers currently recommend PMTCT regimens in the absence of complete data about both the prevalence and severity of mitochondrial toxicity. Although more intensive antiretroviral regimens substantially reduce MTCT among women with low CD4 cell counts, the magnitude of MTCT reduction with three-drug ART compared with shorter-course antiretroviral regimens among women with CD4 cell count more than 200 cells/μl is less well known [11,22,26]. It is also unknown whether exposure to more antiretroviral drugs for longer durations or to specific drugs during particular periods of fetal development causes higher mitochondrial toxicity risk. Because mitochondrial toxicity related to nucleoside reverse transcriptase inhibitors (NRTIs) may be rare and remains controversial, the challenge of identifying the optimal antiretroviral regimen to balance efficacy (reduction in MTCT) with toxicity (pediatric neurologic mitochondrial toxicity) is well suited for assessment by decision analysis [42]. We used the existing data in a decision analytic model to quantify the effects of recommended PMTCT regimens on HIV transmission and neurologic mitochondrial toxicity at 18 months of age for infants in sub-Saharan Africa and to determine the mitochondrial toxicity risk that would warrant a change in current PMTCT recommendations.

Back to Top | Article Outline

Methods

We designed a decision analytic model of pregnant, HIV-infected, ART-naive women in sub-Saharan Africa not meeting 2006 World Health Organization (WHO) criteria for initiation of ART for their own HIV infection (CD4 cell count >200 cells/μl and no history of AIDS) [43]. Using published MTCT and neurologic mitochondrial toxicity risks, we examined the pediatric outcomes at 18 months of age associated with no antiretroviral prophylaxis and with five different recommended PMTCT strategies (Table 1) [43,44].

Table 1
Table 1
Image Tools
Back to Top | Article Outline
Modeled strategies to prevent mother-to-child transmission

For women in resource-limited settings not meeting criteria for ART themselves, WHO recommends four increasingly intensive PMTCT regimens, depending on resource availability [43]. Table 1 outlines the antenatal, intrapartum, and postnatal components of these regimens. We evaluated all WHO-recommended strategies, as well as no antiretroviral drugs (for the purpose of comparison) and protease inhibitor based three-drug ART, as recommended in the United States [44] (Table 1).

The base-case analysis was performed for breastfeeding mothers without access to elective cesarean section. The effects of formula feeding and of the availability and effectiveness of elective cesarean section on reduction in MTCT were evaluated in sensitivity analyses. Model structure is shown in Fig. 1. Additional details are provided in the Technical Appendix.

Fig. 1
Fig. 1
Image Tools
Back to Top | Article Outline
Outcomes/case definitions

Neurologic mitochondrial toxicity was defined according to the Enquête Périnatale Française (EPF) clinical case definition, excluding any requirement for radiographic, biochemical, or histological findings [32] (Technical Appendix). Intrauterine, intrapartum, and postpartum HIV infections were defined according to the timing of first positive infant virologic test (HIV-1 DNA, RNA, or culture), as typically defined for PMTCT trials [7,12,26]. The standard trial definition of intrapartum infection (first positive virologic test between 3 days and 4–8 weeks of age) reflects the limited sensitivity of these assays in the early weeks of life due to delayed viremia [45], but necessitates the inclusion of early postpartum transmission due to breastfeeding in the ‘intrapartum’ category.

Back to Top | Article Outline
Model parameters
HIV transmission risk

In the base-case analysis, risks of HIV transmission for each antiretroviral regimen were derived from publications or presentations meeting the following inclusion criteria: clinical trial of a modeled regimen, conducted in Africa, at least 12 months follow-up, and reporting probabilities of HIV infection at each time point among infants who were HIV-negative at the prior time point (or data that permitted these calculations). Clinical trial-based data were used to inform all analyses. With one exception [23] (Technical Appendix), observational reports were excluded because higher rates of loss to follow-up might bias results. Studies meeting most, but not all, inclusion criteria were included in ranges examined in sensitivity analyses (Technical Appendix Table 1).

For each HIV transmission time point and antiretroviral strategy, the base-case transmission risk was derived from the most widely accepted or cited estimate (based on expert opinion), aiming for the midpoint of the range of reported transmission risks (Table 2) [45–61]. PMTCT data were used to calculate the probability of infection during the intrauterine, intrapartum/early postpartum, and late postpartum periods among children who were uninfected at the previous time point.

Table 2
Table 2
Image Tools

MTCT risks were assigned to either breastfed or formula-fed strategies according to the predominant feeding practice in each trial. For each breastfed strategy, the median duration of breastfeeding was assumed to be equal to that of the trial population (range for base-case analysis, 9 to >20 months) [3,17,27,47,49,54,55]. We simulated extended breastfeeding in order to generate 18-month results applicable to African populations in which this practice is common, and to conservatively estimate the benefits of peripartum antiretroviral drugs, the protective effects of which are likely to fade with prolonged breastfeeding [27].

Back to Top | Article Outline
Neurologic mitochondrial toxicity risk

Because an independent risk of fetal mitochondrial dysfunction has been postulated to result from maternal HIV viremia [39,62], the base-case analysis derived the risk of mitochondrial dysfunction among HIV-exposed but antiretroviral-unexposed children from the upper confidence limit reported in the EPF cohort: 0 of 1748 antiretroviral-unexposed children, 95% confidence interval (CI) (0, 0.17%) [32,63]. Sensitivity analyses evaluated mitochondrial toxicity risks ranging from the general population risk (0.01%) [60,61] to 2.9%, as reported among antiretroviral-exposed children in PACTG 219/219C [2.9%, 95% CI (0.6%–8.4%)] [39] (Table 2).

The risks of mitochondrial toxicity among HIV-exposed and antiretroviral-exposed children were derived from two studies of living, uninfected children incorporating routine neuropsychiatric assessment [32,39]. The base-case analysis made use of the mitochondrial toxicity risks associated with exposure to ZDV (1.88%) and ZDV/3TC (2.04%) at any time during pregnancy in the PACTG 219/219C report [39] (Table 2). Sensitivity analyses incorporated the range of risks reported in these two studies: the overall mitochondrial toxicity risk ranged from 0.26% [32] to 1.8% [39]; when stratified by time of earliest exposure to specific NRTIs, mitochondrial toxicity risks in the PACTG 219/219C cohort ranged from 0.4% (first exposure to 3TC in second trimester) to 6.9% (first exposure to 3TC in third trimester) [39].

Back to Top | Article Outline
Assumptions

When data to inform HIV transmission and neurologic mitochondrial toxicity risks were incomplete for any PMTCT strategy, we assumed differences in transmission or toxicity risks compared to the most similar strategy, based on individual components of each regimen (Table 2; Technical Appendix). In the base-case analysis, because MTCT risks among women with CD4 cell count higher than 200 cells/μl were rarely available [22], we relied on transmission risks from all women participating in the included PMTCT trials (participants reported with CD4 cell count <200 cells/μl: range 5–24%, mean 12.9%). We then used the lowest published transmission risks to create a ‘best case’ scenario for HIV risk which may better reflect MTCT from women with less advanced disease. Adherence to antiretroviral and feeding strategies was assumed to be equal to that in the trials (Table 2).

Back to Top | Article Outline
Sensitivity analyses

Sensitivity analyses were performed on all model parameters and assumptions, including feeding strategy, the availability of elective cesarean section, and all uncertain input parameters (Table 2; Technical Appendix). In order to determine the prevalence of mitochondrial toxicity which would change current practice, we varied the risks of neurologic mitochondrial toxicity associated with each antiretroviral strategy, with individual components of each strategy, and with maternal HIV viremia over published and clinically plausible ranges (Table 2). The highest and lowest published risks of HIV transmission and mitochondrial toxicity were used to create ‘best case’ and ‘worst case’ scenarios for each outcome. The disability of mitochondrial toxicity relative to pediatric HIV infection was also evaluated in sensitivity analyses.

Back to Top | Article Outline

Results

Base-case analysis

Among breastfeeding women, provision of no antiretroviral drugs is the least effective and least toxic PMTCT strategy (HIV transmission risk of 30.4% and mitochondrial toxicity risk of 0.2%, at 18 months of age). With increasing number and duration of antiretroviral drugs, the 18-month HIV transmission risk declines markedly (to 4.9% with three-drug ART). When antepartum NRTIs are used, mitochondrial toxicity risks rise from 0.2% (no antiretroviral drugs; sdNVP) to 2.0% (both scZDV regimens) and 2.2% (three-drug ART). Despite this increased toxicity, three-drug ART minimizes total adverse events, defined as the sum of HIV infections and mitochondrial toxicity cases (Table 3, Section I).

Table 3
Table 3
Image Tools

Using population-level estimates, treating 10 000 breastfeeding mothers with the scZDV/sdNVP/CBV regimen (the next most effective and next least toxic regimen) rather than with three-drug ART would prevent 15 cases of mitochondrial toxicity, but would allow 507 additional HIV infections. To substantially reduce mitochondrial toxicity compared to three-drug ART (0.2 vs. 2.2%), one would choose the sdNVP/CBV regimen; this choice would prevent 202 cases of mitochondrial toxicity in the same population, but 1303 additional HIV infections would occur.

Back to Top | Article Outline
Sensitivity analyses
Formula feeding

When formula-fed infants are evaluated using other base-case parameters, three-drug ART remains the strategy that minimizes total adverse events (Table 3, Section I).

Back to Top | Article Outline
Worst case and best case scenarios

We used the highest published risks of HIV transmission and mitochondrial toxicity associated with each PMTCT regimen to create a ‘worst-case’ (highest toxicity and lowest efficacy) scenario. In contrast to the base case, if the ‘worst case’ risks are simultaneously true for both mitochondrial toxicity and HIV, then both scZDV regimens minimize total adverse outcomes compared to three-drug ART in breastfed and formula-fed infants (Table 3, Section II). When the ‘worst case’ estimates are used only for mitochondrial toxicity risk (Table 3, Section III), the order of strategies is identical to that in the base case for breastfed infants, but both scZDV regimens are superior to three-drug ART in formula-fed infants. When the ‘worst case’ estimates are used only for HIV risk, the order of the strategies is unchanged from the base case, regardless of feeding strategy (Technical Appendix).

When ‘best case’ HIV risks, which may better reflect MTCT risks from mothers with CD4 cell count higher than 200 cells/μl, are combined with base-case mitochondrial toxicity risks, the order of strategies is also unchanged from the base case (Table 3, Section IV). However, when ‘best case’ HIV risks and ‘worst case’ mitochondrial toxicity risks are simultaneously examined, the less-intensive regimens (scZDV/sdNVP/CBV in breastfed infants (Table 3, Section V), and all antiretroviral regimens in formula-fed infants (Technical Appendix)) minimize total adverse outcomes, compared to three-drug ART.

Back to Top | Article Outline
Relative disability of mitochondrial toxicity and HIV

We varied the degree of disability associated with neurologic mitochondrial toxicity as a function of the disability associated with pediatric HIV (Fig. 2) and compared the total adverse pediatric outcomes (HIV and mitochondrial toxicity) associated with each strategy. Using the base-case input parameters, we first compared three-drug ART to the most effective regimen that excludes an NRTI, conferring a substantial decrease in toxicity (sdNVP/CBV). In breastfed infants, the morbidity of mitochondrial toxicity would be more than 6.4 times the morbidity of pediatric HIV infection to recommend the sdNVP/CBV regimen over three-drug ART (open arrow). We then compared three-drug ART to the next most effective and next least toxic regimen (scZDV/sdNVP/CBV). Here, the threshold is higher, because the number of excess cases of HIV that occur when the scZDV/sdNVP/CBV regimen is substituted for three-drug ART greatly exceeds the number of mitochondrial toxicity cases prevented: the morbidity of mitochondrial toxicity would need to be more than 32.1 times that of HIV in breastfed infants in order to recommend the scZDV/sdNVP/CBV regimen over three-drug ART (closed arrow).

Fig. 2
Fig. 2
Image Tools
Back to Top | Article Outline

Discussion

The efficacy of antiretroviral drugs in the prevention of MTCT of HIV is widely accepted [64]. Two studies report an association between in-utero antiretroviral exposure and infant neurologic dysfunction possibly related to mitochondrial toxicity [32,39], but the true prevalence and severity of this postulated mitochondrial toxicity remain controversial [65,66]. Motivated by the possibility that the association between antiretroviral exposure and mitochondrial toxicity is causal [39], we conducted an exploratory analysis in order to determine the prevalence and severity of mitochondrial toxicity at which current antiretroviral recommendations for PMTCT would merit change [43,44].

This decision analytic model assesses the 18-month risks for pediatric HIV transmission and neurologic mitochondrial toxicity, following the administration of six different PMTCT regimens to pregnant, HIV-infected women in sub-Saharan Africa. Model results reflect the published efficacy of antiretroviral drugs for PMTCT; base-case estimates of HIV transmission at 18 months in breastfed infants range from 4.9% with three-drug ART to 30.4% with no antiretroviral drugs. These results calibrate with results from observational studies [67,68] and with syntheses of PMTCT trials in sub-Saharan Africa [3,18,69,70], including 40–50% (relative) [59,69] and 14–15% (absolute) [69,71,72] increases in MTCT risk due to breastfeeding. Because mitochondrial toxicity 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, three-drug ART initiated in the first trimester results in many fewer pediatric HIV infections, slightly more cases of pediatric neurologic mitochondrial toxicity, and substantially fewer total adverse pediatric outcomes (HIV infections and mitochondrial toxicity cases) than the less toxic but less effective regimens.

Published studies of antiretroviral-associated mitochondrial toxicity have differed in methodology and mitochondrial toxicity case definition, which may explain inconsistent findings [2,5,29–38,40,73–78]. In addition, most studies have not controlled for maternal substance abuse and socioeconomic factors [77], 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 [39,62,77]. We therefore chose data from the only two studies using routine neuropsychiatric evaluations of living, HIV-uninfected children [32,39]. Brogly et al. [39] demonstrated a significantly higher risk of mitochondrial toxicity when NRTIs (ZDV, 3TC, or both) were initiated in the third trimester than when they are initiated in the first trimester. They postulate a period of neurodevelopment late in gestation in which the fetal brain is uniquely sensitive to NRTI-induced mitochondrial toxicity [79–81]. The authors were unable to control for high maternal RNA at delivery (likely a result of late antiretroviral initiation) and maternal drug use (a potential cause of late antiretroviral initiation, although not associated with mitochondrial toxicity in this study). Because these factors may have led to the overestimation of mitochondrial toxicity risk from third-trimester NRTI initiation, our base-case analysis conservatively relied on the mitochondrial toxicity risk associated with any ZDV, 3TC, or ZDV/3TC exposure, regardless of timing (1.88–2.04%).

Our results demonstrate that at mitochondrial toxicity prevalences lower than the base-case risks (as in the EPF, range 0.26–0.87%) [32], three-drug ART would still minimize total adverse outcomes. More importantly, these results remain true at mitochondrial toxicity prevalences higher than the base-case scenario. Our ‘worst-case’ mitochondrial toxicity scenario used data from subgroups with third-trimester initiation of ZDV, 3TC, or ZDV/3TC in PACTG 219/219C; results suggest that even if these ‘worst-case’ mitochondrial toxicity estimates were correct, a change in recommended antiretroviral drugs 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 [1,8,18,23,26,57,69].

Currently reported prevalences of mitochondrial toxicity are therefore unlikely to change PMTCT recommendations. However, little is known about the morbidity and mortality of antiretroviral-associated neurologic mitochondrial toxicity [32,39,40,65], and prognostic information must be extrapolated from reports of congenital mitochondrial dysfunction [60,61,82,83]. As new data specific to antiretroviral-associated mitochondrial toxicity emerge [4,32,39,40,65,84], a primary factor in the choice of PMTCT regimen will be the relative disability of mitochondrial toxicity compared to that of pediatric HIV infection. Pediatric HIV disease substantially reduces life expectancy in sub-Saharan Africa, even when therapy is available [85–88], and may itself be associated with significant neurodevelopmental delay [89]. If pediatric HIV infection consistently causes greater morbidity and mortality than does mitochondrial toxicity, then the balance of risk and benefit will always favor more effective regimens for PMTCT. If, however, mitochondrial toxicity is markedly more disabling than pediatric HIV (e.g., 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 mitochondrial toxicity in uninfected children. The combined outcome of HIV infections and mitochondrial toxicity cases allowed us to estimate that, at base-case mitochondrial toxicity risks, neurologic mitochondrial toxicity would 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 cell count higher than 200 cells/μl, as reflected in recent changes to US treatment guidelines [90]. Therefore, women included in our model are likely to benefit from three-drug ART during pregnancy, and the effects on maternal health of withdrawing ART after use for PMTCT remain unknown [44,91,92]. Maternal drug-resistant HIV resulting from single-drug or dual-drug PMTCT regimens may also result in reduced efficacy of ART when it is eventually initiated [93]. These maternal effects may tip the balance of risk and benefit in favor of three-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-affected or mitochondrial toxicity affected children after birth. In settings with severely constrained healthcare resources, concerns for costs may outweigh concerns for toxicity in the selection of antiretroviral regimens for PMTCT.

This analysis required several simplifying assumptions. First, data are limited on late postpartum transmission rates by actual infant feeding practices [7,17,68]. 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 [94]. Finally, women with CD4 cell count less than 200 cells/μl merit three-drug ART for their own HIV infections as well as for PMTCT [43], and therefore were intentionally excluded from the model. Because available MTCT data were not limited to women with high CD4 cell counts, the base-case analysis likely overestimates transmission risks for women not requiring ART themselves [19,95].

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 mitochondrial toxicity risks for three-drug ART were simultaneously considered. For breastfed infants in this ‘best case HIV/worst case mitochondrial toxicity’ scenario, scZDV/sdNVP/CBV was superior to three-drug ART, due primarily to the high mitochondrial toxicity risk assigned to third-trimester 3TC exposure. For formula-fed infants, all antiretroviral regimens were superior to three-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 confirm whether scZDV regimens are effective among women with CD4 cell count higher than 200 cells/μl, and whether mitochondrial toxicity risks with three-drug ART approach those observed in the highest-risk subgroups of PACTG 219/219C [39]. If such data emerge and are simultaneously true, short-course regimens may be appropriate alternatives to three-drug ART in women with high CD4 cell 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 antiretroviral 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 protease inhibitor-based three-drug ART for PMTCT. Less-effective antiretroviral regimens would only be substantially superior to three-drug ART if the very highest or lowest published risks of HIV, as well as the highest published risks of mitochondrial toxicity, associated with each strategy were simultaneously true, or if antiretroviral-related mitochondrial toxicity were markedly more disabling than pediatric HIV infection. Access to diagnosis, prenatal care, and antiretroviral drugs 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 three-drug ART to women who require therapy for their own health [64]. 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 three-drug ART during pregnancy for PMTCT, and efforts should be expanded to increase the availability of three-drug ART for PMTCT in resource-limited settings.

Back to Top | Article Outline

Acknowledgements

The authors gratefully acknowledge Jennifer Chu, BS, and Brandon Morris, BA, for assistance with manuscript preparation. Funding for this work was provided by the National Institute of Allergy and Infectious Disease [T32 AI07433 (A.L.C.; PI: K.A.F.); R01 AI058736 and R37 AI42006-10A1 (K.A.F., M.C.W., R.P.W.); and U01 AI 069456-01 (S.L.)]; the National Institute of Child Health and Human Development [Cooperative Agreement U01 HD052102-03 (G.R.S.); R01 HD044391 (S.L.)]; and the Doris Duke Charitable Foundation [Clinical Scientist Development Award (R.P.W.)].

Author contributions include formulation of the research question (A.L.C., K.A.F., S.L., G.R.S., R.P.W.), design of the simulation model and analytic plan (A.L.C., K.A.F., M.C.W., R.P.W.), selection of the input data for simulation model (A.L.C., S.L., R.P.W.), and preparation (A.L.C.) and critical editing (K.A.F., S.L., G.R.S., M.C.W., R.P.W.) of the manuscript.

There is no conflict of interests.

This work was presented in poster form at the May 2007 Harvard University Center for AIDS Research Pediatric HIV Symposium (Boston, Massachusetts, USA) and at the October 2007 Annual Meeting of the Society for Medical Decision Making (Pittsburgh, Pennsylvania, USA). Additional information regarding model structure, input parameters, and results has been included in a Technical Appendix, which can be accessed online at http://www.aidsonline.com.

Back to Top | Article Outline

References

1. Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O'Sullivan MJ, et al. Reduction of maternal–infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med 1994; 331:1173–1180.

2. Dominguez K, Bertolli J, Fowler M, Peters V, Ortiz I, Melville S, et al. Lack of definitive severe mitochondrial signs and symptoms among deceased HIV-uninfected and HIV-indeterminate children < or = 5 years of age, Pediatric Spectrum of HIV Disease project (PSD), USA. Ann N Y Acad Sci 2000; 918:236–246.

3. Leroy V, Karon JM, Alioum A, Ekpini ER, Meda N, Greenberg AE, et al. Twenty-four month efficacy of a maternal short-course zidovudine regimen to prevent mother-to-child transmission of HIV-1 in West Africa. AIDS 2002; 16:631–641.

4. Cooper ER, Charurat M, Mofenson L, Hanson IC, Pitt J, Diaz C, et al. Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and prevention of perinatal HIV-1 transmission. J Acquir Immune Defic Syndr 2002; 29:484–494.

5. Petra Study Team. Efficacy of three short-course regimens of zidovudine and lamivudine in preventing early and late transmission of HIV-1 from mother to child in Tanzania, South Africa, and Uganda (Petra study): a randomised, double-blind, placebo-controlled trial. Lancet 2002; 359:1178–1186.

6. McIntyre JA, Martinson N, Gray GE, Hopley M, Kimura T, Robinson P, Mayers D. Addition of short course Combivir (CBV) to single dose Viramune (sdNVP) for the prevention of mother to child transmission (pMTCT) of HIV-1 can significantly decrease the subsequent development of maternal and paediatric NNRTI-resistant virus [Abstract no. TuFo0204]. International AIDS Society. Rio de Janeiro; 2005.

7. Guay LA, Musoke P, Fleming T, Bagenda D, Allen M, Nakabiito C, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 1999; 354:795–802.

8. Lallemant M, Jourdain G, Le Coeur S, Mary JY, Ngo-Giang-Huong N, Koetsawang S, et al. Single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of HIV-1 in Thailand. N Engl J Med 2004; 351:217–228.

9. Lallemant M, Jourdain G, Le Coeur S, Kim S, Koetsawang S, Comeau AM, et al. A trial of shortened zidovudine regimens to prevent mother-to-child transmission of human immunodeficiency virus type 1. Perinatal HIV Prevention Trial (Thailand) Investigators. N Engl J Med 2000; 343:982–991.

10. Mandelbrot L, Landreau-Mascaro A, Rekacewicz C, Berrebi A, Benifla JL, Burgard M, et al. Lamivudine–zidovudine combination for prevention of maternal–infant transmission of HIV-1. JAMA 2001; 285:2083–2093.

11. Dabis F, Bequet L, Ekouevi DK, Viho I, Rouet F, Horo A, et al. Field efficacy of zidovudine, lamivudine and single-dose nevirapine to prevent peripartum HIV transmission. AIDS 2005; 19:309–318.

12. Dorenbaum A, Cunningham CK, Gelber RD, Culnane M, Mofenson L, Britto P, et al. Two-dose intrapartum/newborn nevirapine and standard antiretroviral therapy to reduce perinatal HIV transmission: a randomized trial. JAMA 2002; 288:189–198.

13. Thistle P, Gottesman M, Pilon R, Glazier RH, Arbess G, Phillips E, et al. A randomized control trial of an Ultra-Short zidovudine regimen in the prevention of perinatal HIV transmission in rural Zimbabwe. Cent Afr J Med 2004; 50:79–84.

14. Shaffer N, Chuachoowong R, Mock PA, Bhadrakom C, Siriwasin W, Young NL, et al. Short-course zidovudine for perinatal HIV-1 transmission in Bangkok, Thailand: a randomised controlled trial. Bangkok Collaborative Perinatal HIV Transmission Study Group. Lancet 1999; 353:773–780.

15. Moodley D, Moodley J, Coovadia H, Gray G, McIntyre J, Hofmyer J, et al. A multicenter randomized controlled trial of nevirapine versus a combination of zidovudine and lamivudine to reduce intrapartum and early postpartum mother-to-child transmission of human immunodeficiency virus type 1. J Infect Dis 2003; 187:725–735.

16. Taha TE, Kumwenda NI, Hoover DR, Fiscus SA, Kafulafula G, Nkhoma C, et al. Nevirapine and zidovudine at birth to reduce perinatal transmission of HIV in an African setting: a randomized controlled trial. JAMA 2004; 292:202–209.

17. Nduati R, John G, Mbori-Ngacha D, Richardson B, Overbaugh J, Mwatha A, et al. Effect of breastfeeding and formula feeding on transmission of HIV-1: a randomized clinical trial. JAMA 2000; 283:1167–1174.

18. Leroy V, Sakarovitch C, Cortina-Borja M, McIntyre J, Coovadia H, Dabis F, et al. Is there a difference in the efficacy of peripartum antiretroviral regimens in reducing mother-to-child transmission of HIV in Africa? AIDS 2005; 19:1865–1875.

19. Kumwenda NI, Hoover DR, Mofenson LM, Thigpen MC, Kafulafula G, Li Q, et al. Extended antiretroviral prophylaxis to reduce breast-milk HIV-1 transmission. N Engl J Med 2008; 359:119–129.

20. Sastry J, and The Six Week Extended Dose Nevirapine (SWEN) Study Team. Extended-dose nevirapine to 6 weeks of age for infants in Ethiopia, India, and Uganda: a randomized trial for prevention of HIV transmission through breastfeeding [Abstract 43]. Proceedings of the Conference on Retroviruses and Opportunistic Infections; Boston; 2008.

21. Bedri A, Gudetta B, Isehak A, Kumbi S, Lulseged S, Mengistu Y, et al. Extended-dose nevirapine to 6 weeks of age for infants to prevent HIV transmission via breastfeeding in Ethiopia, India, and Uganda: an analysis of three randomised controlled trials. Lancet 2008; 372:300–313.

22. Thomas T, Masaba R, Ndivo R, Zeh C, Borkowf C, Thigpen M, et al., and Kisumu Breastfeeding Study Team. Prevention of mother-to-child transmission of HIV-1 among breastfeeding mothers using HAART: The Kisumu Breastfeeding Study, Kisumu, Kenya, 2003–2007 [Abstract 45aLB]. Proceedings of the Conference on Retroviruses and Opportunistic Infections; Boston; 2008.

23. Palombi L, Marazzi MC, Voetberg A, Magid NA. Treatment acceleration program and the experience of the DREAM program in prevention of mother-to-child transmission of HIV. AIDS 2007; 21(Suppl 4):S65–S71.

24. Kilewo C, Karlsson K, Ngarina M, Massawe A, Lyamuya E, Lipyoga R, et al. Prevention of mother-to-child transmission of HIV-1 through breastfeeding by treating mothers prophylactically with triple antiretroviral therapy in Dar es Salaam, Tanzania – the MITRA PLUS study. International AIDS Society. Sydney, Australia; 2007.

25. Arendt V, Ndimubanzi P, Vyankandondera J, Ndayisaba G, Muganda J, Courteille O, et al. AMATA study: effectiveness of antiretroviral therapy in breastfeeding mothers to prevent postnatal vertical transmission in Rwanda. International AIDS Society. Sydney, Australia; 2007.

26. Thior I, Lockman S, Smeaton LM, Shapiro RL, Wester C, Heymann SJ, et al. Breastfeeding plus infant zidovudine prophylaxis for 6 months vs formula feeding plus infant zidovudine for 1 month to reduce mother-to-child HIV transmission in Botswana: a randomized trial: the Mashi Study. JAMA 2006; 296:794–805.

27. Jackson JB, Musoke P, Fleming T, Guay LA, Bagenda D, Allen M, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012 randomised trial. Lancet 2003; 362:859–868.

28. Blanche S, Tardieu M, Rustin P, Slama A, Barret B, Firtion G, et al. Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet 1999; 354:1084–1089.

29. Aldrovandi G, Moye J, Chu C, Ha B, Handelsman E, Shearer W, et al., for the WITS Study Group. Mitochondrial DNA content of peripheral blood mononuclear cells in uninfected infants born to HIV-infected women with or without ART exposure in the Women and Infants Transmission Study [Paper #695]. Conference on Retroviruses and Opportunistic Infections; Denver; 2006.

30. Vigano A, Bianchi R, Schneider L, Cafarelli L, Tornaghi R, Pinti M, et al. Lack of hyperlactatemia and impaired mitochondrial DNA content in CD4+ cells of HIV-uninfected infants exposed to perinatal antiretroviral therapy [Paper #942]. Proceedings of the Conference on Retroviruses and Opportunistic Infections; San Francisco; 2004.

31. Maagaard A, Holberg-Petersen M, Kollberg G, Oldfors A, Sandvik L, Bruun JN. Mitochondrial (mt)DNA changes in tissue may not be reflected by depletion of mtDNA in peripheral blood mononuclear cells in HIV-infected patients. Antivir Ther 2006; 11:601–608.

32. Barret B, Tardieu M, Rustin P, Lacroix C, Chabrol B, Desguerre I, et al. Persistent mitochondrial dysfunction in HIV-1-exposed but uninfected infants: clinical screening in a large prospective cohort. AIDS 2003; 17:1769–1785.

33. Culnane M, Fowler M, Lee SS, McSherry G, Brady M, O'Donnell K, et al. Lack of long-term effects of in utero exposure to zidovudine among uninfected children born to HIV-infected women. Pediatric AIDS Clinical Trials Group Protocol 219/076 Teams. JAMA 1999; 281:151–157.

34. Le Chenadec J, Mayaux MJ, Guihenneuc-Jouyaux C, Blanche S. Perinatal antiretroviral treatment and hematopoiesis in HIV-uninfected infants. AIDS 2003; 17:2053–2061.

35. O'Meara M, Goode M, Hayes E, Butler K. Simplification of neonatal component of regimens to prevent perinatal HIV transmission [Abstract #853]. Proceedings of the Conference on Retroviruses and Opportunistic Infections; Boston; 2003.

36. Noguera A, Fortuny C, Munoz-Almagro C, Sanchez E, Vilaseca MA, Artuch R, et al. Hyperlactatemia in human immunodeficiency virus-uninfected infants who are exposed to antiretrovirals. Pediatrics 2004; 114:e598–e603.

37. Giaquinto C, De Romeo A, Giacomet V, Rampon O, Ruga E, Burlina A, et al. Lactic acid levels in children perinatally treated with antiretroviral agents to prevent HIV transmission. AIDS 2001; 15:1074–1075.

38. Ekouevi DK, Toure R, Becquet R, Viho I, Sakarovitch C, Rouet F, et al. Serum lactate levels in infants exposed peripartum to antiretroviral agents to prevent mother-to-child transmission of HIV: Agence Nationale de Recherches Sur le SIDA et les Hepatites Virales 1209 study, Abidjan. Ivory Coast Pediatrics 2006; 118:e1071–e1077.

39. Brogly S, Ylitalo N, Mofenson L, Oleskee J, Van Dyke R, Craing M, et al. In utero nucleoside reverse transcriptase inhibitor exposure and signs of possible mitochondrial dysfunction in HIV-uninfected children. AIDS 2007; 21:929–938.

40. European Collaborative Study. Exposure to antiretroviral therapy in utero or early life: the health of uninfected children born to HIV-infected women. J Acquir Immune Defic Syndr 2003; 32:380–387.

41. Benhammou V, Tardieu M, Warszawski J, Rustin P, Blanche S. Clinical mitochondrial dysfunction in uninfected children born to HIV-infected mothers following perinatal exposure to nucleoside analogues. Environ Mol Mutagen 2007; 48:173–178.

42. Hunink M, Glasziou PP, Siegel JE, Weeks JC, Pliskin JS, Elstein AS, Weinstein MC. Decision making in health and medicine: integrating evidence and values. Cambridge: Cambridge University Press; 2003.

43. World Health Organization. Antiretroviral drugs for treating pregnant women and preventing HIV infections in infants in resource-limited settings: towards universal access: recommendations for a public health approach; 2006. http://www.who.int/hiv/pub/guidelines/en/. Accessed 15 October 2006. July 15, 2008.

44. US Public Health Service Task Force. Perinatal HIV Guidelines Working Group. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States; 2008. http://aidsinfo.nih.gov/contentfiles/PerinatalGL.pdf.

45. Feeney ME, Tang Y, Pfafferott K, Roosevelt KA, Draenert R, Trocha A, et al. HIV-1 viral escape in infancy followed by emergence of a variant-specific CTL response. J Immunol 2005; 174:7524–7530.

46. Massad LS, Springer G, Jacobson L, Watts H, Anastos K, Korn A, et al. Pregnancy rates and predictors of conception, miscarriage and abortion in US women with HIV. AIDS 2004; 18:281–286.

47. Coutsoudis A, Pillay K, Kuhn L, Spooner E, Tsai WY, Coovadia HM. Method of feeding and transmission of HIV-1 from mothers to children by 15 months of age: prospective cohort study from Durban, South Africa. AIDS 2001; 15:379–387.

48. Kuhn L, Aldrovandi GM, Sinkala M, Kankasa C, Semrau K, Mwiya M, et al. Effects of early, abrupt weaning on HIV-free survival of children in Zambia. N Engl J Med 2008; 359:130–141.

49. Taha TE, Hoover DR, Kumwenda NI, Fiscus SA, Kafulafula G, Nkhoma C, et al. Late postnatal transmission of HIV-1 and associated factors. J Infect Dis 2007; 196:10–14.

50. Magder LS, Mofenson L, Paul ME, Zorrilla CD, Blattner WA, Tuomala RE, et al. Risk factors for in utero and intrapartum transmission of HIV. J Acquir Immune Defic Syndr 2005; 38:87–95.

51. Dabis F, Msellati P, Meda N, Welffens-Ekra C, You B, Manigart O, et al. 6-month efficacy, tolerance, and acceptability of a short regimen of oral zidovudine to reduce vertical transmission of HIV in breastfed children in Cote d'Ivoire and Burkina Faso: a double-blind placebo-controlled multicentre trial. DITRAME Study Group. DIminution de la Transmission Mere-Enfant. Lancet 1999; 353:786–792.

52. Coutsoudis A, Pillay K, Spooner E, Kuhn L, Coovadia HM. Influence of infant-feeding patterns on early mother-to-child transmission of HIV-1 in Durban, South Africa: a prospective cohort study. South African Vitamin A Study Group. Lancet 1999; 354:471–476.

53. Thistle P, Spitzer RF, Glazier RH, Pilon R, Arbess G, Simor A, et al. A randomized, double-blind, placebo-controlled trial of combined nevirapine and zidovudine compared with nevirapine alone in the prevention of perinatal transmission of HIV in Zimbabwe. Clin Infect Dis 2007; 44:111–119.

54. Fawzi W, Msamanga G, Spiegelman D, Renjifo B, Bang H, Kapiga S, et al. Transmission of HIV-1 through breastfeeding among women in Dar es Salaam, Tanzania. J Acquir Immune Defic Syndr 2002; 31:331–338.

55. Iliff PJ, Piwoz EG, Tavengwa NV, Zunguza CD, Marinda ET, Nathoo KJ, et al. Early exclusive breastfeeding reduces the risk of postnatal HIV-1 transmission and increases HIV-free survival. AIDS 2005; 19:699–708.

56. Chi BH, Chintu N, Cantrell RA, Kankasa C, Kruse G, Mbewe F, et al. Addition of single-dose tenofovir and emtricitabine to intrapartum nevirapine to reduce perinatal HIV transmission. J Acquir Immune Defic Syndr 2008; 48:220–223.

57. Jamisse L, Balkus J, Farquhar C, Osman N, Djedje M, Hitti J. Perinatal HIV transmission with HAART during late pregnancy and postpartum [Abstract 756]. Proceedings of the Conference on Retroviruses and Opportunistic Infections; Los Angeles; 2007.

58. Palombi L, Germano P, Liotta G, Magnano san Lio M, Guidotti G, Assane A, et al. Safety and efficacy of maternal HAART in the prevention of early and late postnatal HIV-1 transmission in Mozambique [Paper #747]. Proceedings of the Conference on Retroviruses and Opportunistic Infections; Los Angeles; 2007.

59. Coutsoudis A, Dabis F, Fawzi W, Gaillard P, Haverkamp G, Harris DR, et al. Late postnatal transmission of HIV-1 in breast-fed children: an individual patient data meta-analysis. J Infect Dis 2004; 189:2154–2166.

60. Uusimaa J, Remes AM, Rantala H, Vainionpaa L, Herva R, Vuopala K, et al. Childhood encephalopathies and myopathies: a prospective study in a defined population to assess the frequency of mitochondrial disorders. Pediatrics 2000; 105:598–603.

61. Darin N, Oldfors A, Moslemi AR, Holme E, Tulinius M. The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA anbormalities. Ann Neurol 2001; 49:377–383.

62. Poirier MC, Divi RL, Al-Harthi L, Olivero OA, Nguyen V, Walker B, et al. Long-term mitochondrial toxicity in HIV-uninfected infants born to HIV-infected mothers. J Acquir Immune Defic Syndr 2003; 33:175–183.

63. Eypasch E, Lefering R, Kum CK, Troidl H. Probability of adverse events that have not yet occurred: a statistical reminder. BMJ 1995; 311:619–620.

64. World Health Organization. Mother-to-child transmission of HIV; 2007. http://www.who.int/hiv/mtct/en/index.html. Accessed 23 May 2007.

65. Spector SA, Saitoh A. Mitochondrial dysfunction: prevention of HIV-1 mother-to-infant transmission outweighs fear. AIDS 2006; 20:1777–1778.

66. Blanche S, Tardieu M, Benhammou V, Warszawski J, Rustin P. Mitochondrial dysfunction following perinatal exposure to nucleoside analogues. AIDS 2006; 20:1685–1690.

67. Tonwe-Gold B, Ekouevi DK, Viho I, Amani-Bosse C, Toure S, Coffie PA, et al. Antiretroviral treatment and prevention of peripartum and postnatal HIV transmission in West Africa: evaluation of a two-tiered approach. PLoS Med 2007; 4:e257.

68. Coovadia HM, Rollins NC, Bland RM, Little K, Coutsoudis A, Bennish ML, Newell ML. Mother-to-child transmission of HIV-1 infection during exclusive breastfeeding in the first 6 months of life: an intervention cohort study. Lancet 2007; 369:1107–1116.

69. De Cock KM, Fowler MG, Mercier E, De Vincenzi I, Saba J, Hoff E, et al. Prevention of mother-to-child HIV transmission in resource-poor countries: translating research into policy and practice. JAMA 2000; 283:1175–1182.

70. Chigwedere P, Seage GR, Lee TH, Essex M. Efficacy of antiretroviral drugs in reducing mother-to-child transmission of HIV in Africa: a meta-analysis of published clinical trials. AIDS Res Hum Retroviruses 2008; 24:827–837.

71. Kourtis AP, Lee FK, Abrams EJ, Jamieson DJ, Bulterys M. Mother-to-child transmission of HIV-1: timing and implications for prevention. Lancet Infect Dis 2006; 6:726–732.

72. Dunn DT, Newell ML, Ades AE, Peckham CS. Risk of human immunodeficiency virus type 1 transmission through breastfeeding. Lancet 1992; 340:585–588.

73. Bulterys M, Nesheim S, Abrams EJ, Palumbo P, Farley J, Lampe M, Fowler MG. Lack of evidence of mitochondrial dysfunction in the offspring of HIV-infected women. Retrospective review of perinatal exposure to antiretroviral drugs in the Perinatal AIDS Collaborative Transmission Study. Ann N Y Acad Sci 2000; 918:212–221.

74. 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 2000; 25:261–268.

75. Tovo PA, Chiapello N, Gabiano C, Zeviani M, Spada M. Zidovudine administration during pregnancy and mitochondrial disease in the offspring. Antivir Ther 2005; 10:697–699.

76. Chotpitayasunondh T, Vanprapar N, Simonds RJ, Chokephaibulkit K, Waranawat N, Mock P, et al. Safety of late in utero exposure to zidovudine in infants born to human immunodeficiency virus-infected mothers: Bangkok. Bangkok Collaborative Perinatal HIV Transmission Study Group. Pediatrics 2001; 107:E5.

77. Alimenti A, Forbes JC, Oberlander TF, Money DM, Grunau RE, Papsdorf MP, et al. A prospective controlled study of neurodevelopment in HIV-uninfected children exposed to combination antiretroviral drugs in pregnancy. Pediatrics 2006; 118:e1139–e1145.

78. Paul ME, Chantry CJ, Read JS, Frederick MM, Lu M, Pitt J, et al. Morbidity and mortality during the first two years of life among uninfected children born to human immunodeficiency virus type 1-infected women: the women and infants transmission study. Pediatr Infect Dis J 2005; 24:46–56.

79. Divi RL, Haverkos KJ, Humsi JA, Shockley ME, Thamire C, Nagashima K, et al. Morphological and molecular course of mitochondrial pathology in cultured human cells exposed long-term to Zidovudine. Environ Mol Mutagen 2007; 48:179–189.

80. Divi RL, Leonard SL, Kuo MM, Nagashima K, Thamire C, St Claire MC, et al. Transplacentally exposed human and monkey newborn infants show similar evidence of nucleoside reverse transcriptase inhibitor-induced mitochondrial toxicity. Environ Mol Mutagen 2007; 48:201–209.

81. Venerosi A, Valanzano A, Alleva E, Calamandrei G. Prenatal exposure to anti-HIV drugs: neurobehavioral effects of zidovudine (AZT) + lamivudine (3TC) treatment in mice. Teratology 2001; 63:26–37.

82. Schapira AH. Mitochondrial disease. Lancet 2006; 368:70–82.

83. Haas R, Dietrich R. Neuroimaging of mitochondrial disorders. Mitochondrion 2004; 4:471–490.

84. National Institute of Child Health and Human Development. Pediatric HIV/AIDS Cohort Study Home Page; 2007. http://phacs.nichdclinicalstudies.org/overview.asp.

85. Newell ML, Coovadia H, Cortina-Borja M, Rollins N, Gaillard P, Dabis F. Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis. Lancet 2004; 364:1236–1243.

86. Fassinou P, Elenga N, Rouet F, Laguide R, Kouakoussui KA, Timite M, et al. Highly active antiretroviral therapies among HIV-1-infected children in Abidjan, Cote d'Ivoire. AIDS 2004; 18:1905–1913.

87. Violari A, Cotton M, Gibb D, Babiker A, Steyn J, Jean-Phillip P, McIntyre J. Antiretroviral therapy initiated before 12 weeks of age reduces early mortality in young HIV-infected infants: evidence from the Children with HIV Early Antiretroviral Therapy (CHER) Study. International AIDS Society; Sydney, Australia; 2007.

88. Bolton-Moore C, Mubiana-Mbewe M, Cantrell RA, Chintu N, Stringer EM, Chi BH, et al. Clinical outcomes and CD4 cell response in children receiving antiretroviral therapy at primary healthcare facilities in Zambia. JAMA 2007; 298:1888–1899.

89. Foster CJ, Biggs RL, Melvin D, Walters MD, Tudor-Williams G, Lyall EG. Neurodevelopmental outcomes in children with HIV infection under 3 years of age. Dev Med Child Neurol 2006; 48:677–682.

90. Hammer SM, Eron JJ Jr, Reiss P, Schooley RT, Thompson MA, Walmsley S, et al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society – USA Panel. JAMA 2008; 300:555–570.

91. El-Sadr WM, Lundgren JD, Neaton JD, Gordin F, Abrams D, Arduino RC, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006; 355:2283–2296.

92. Lundgren JD, Babiker A, El-Sadr W, Emery S, Grund B, Neaton JD, et al. Inferior clinical outcome of the CD4+ cell count-guided antiretroviral treatment interruption strategy in the SMART study: role of CD4+ Cell counts and HIV RNA levels during follow-up. J Infect Dis 2008; 197:1145–1155.

93. Lockman S, Shapiro RL, Smeaton LM, Wester C, Thior I, Stevens L, et al. Response to antiretroviral therapy after a single, peripartum dose of nevirapine. N Engl J Med 2007; 356:135–147.

94. Llorente A, Brouwers P, Charurat M, Magder L, Malee K, Mellins C, et al. Early neurodevelopmental markers predictive of mortality in infants infected with HIV-1. Dev Med Child Neurol 2003; 45:76–84.

95. Rouet F, Sakarovitch C, Msellati P, Elenga N, Montcho C, Viho I, et al. Pediatric viral human immunodeficiency virus type 1 RNA levels, timing of infection, and disease progression in African HIV-1-infected children. Pediatrics 2003; 112:e289.

Cited By:

This article has been cited 2 time(s).

Clinical Infectious Diseases
Prevention in Neglected Subpopulations: Prevention of Mother-to-Child Transmission of HIV Infection
Mofenson, LM
Clinical Infectious Diseases, 50(): S130-S148.
10.1086/651484
CrossRef
Cochrane Database of Systematic Reviews
Antiretroviral therapy (ART) for treating HIV infection in ART-eligible pregnant women
Sturt, AS; Dokubo, EK; Sint, TT
Cochrane Database of Systematic Reviews, (3): -.
ARTN CD008440
CrossRef
Back to Top | Article Outline
Keywords:

antiretroviral therapy; decision analysis; HIV/AIDS; mitochondrial toxicity; pediatric HIV; PMTCT; sub-Saharan Africa

Fig. 1
Fig. 1
Image Tools
Fig. 2
Fig. 2
Image Tools
Fig. 3
Fig. 3
Image Tools
Fig. 4
Fig. 4
Image Tools
Fig. 5
Fig. 5
Image Tools
Fig. 6
Fig. 6
Image Tools
Fig. 7
Fig. 7
Image Tools
Fig. 8
Fig. 8
Image Tools
Fig. 9
Fig. 9
Image Tools

© 2008 Lippincott Williams & Wilkins, Inc.

Login

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.