# Contribution of Maternal Antiretroviral Therapy and Breastfeeding to 24-Month Survival in Human Immunodeficiency Virus-Exposed Uninfected Children: An Individual Pooled Analysis of African and Asian Studies

Shino Arikawa, Nigel Rollins, Gonzague Jourdain, Jean Humphrey, Athena P. Kourtis, Irving Hoffman, Max Essex, Tim Farley, Hoosen M. Coovadia,

Glenda Gray, et al.

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Shino Arikawa, Nigel Rollins, Gonzague Jourdain, Jean Humphrey, Athena P. Kourtis, et al. Contribution of Maternal Antiretroviral Therapy and Breastfeeding to 24-Month Survival in Human Immunodeficiency Virus-Exposed Uninfected Children: An Individual Pooled Analysis of African and Asian Studies. Clinical Infectious Diseases, In press, 66 (11), pp.1668-1677. 10.1093/cid/cix1102. hal-02881472

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# Contribution of Maternal Antiretroviral Therapy and Breastfeeding to 24-Month Survival in Human Immunodeficiency Virus-Exposed Uninfected Children: An Individual Pooled Analysis of African and Asian Studies

Shino Arikawa,<fnref n="1" /> Nigel Rollins,² Gonzague Jourdain,³,⁴,⁵ Jean Humphrey,⁶ Athena P. Kourtis,⁷,⁸ Irving Hoffman,⁹ Max Essex,⁵ Tim Farley,¹⁰,¹⁰a

Hoosen M. Coovadia,¹¹ Glenda Gray,<fnref n="1" />,²,¹³ Louise Kuhn,¹⁴ Roger Shapiro,⁵ Valériane Leroy,¹⁵ Robert C. Bollinger,¹⁶ Carolyne Onyango-Makumbi,¹⁷

Shahin Lockman,⁵ Carina Marquez,¹⁸ Tanya Doherty,¹² François Dabis,<fnref n="1" /> Laurent Mandelbrot,¹⁹ Sophie Le Coeur,³,⁴,⁵,²⁰ Matthieu Rolland,<fnref n="1" /> Pierre Joly,²¹

Marie-Louise Newell,²² and Renaud Becquet<fnref n="1" />

**Background.** Human immunodeficiency virus (HIV)–infected pregnant women increasingly receive antiretroviral therapy (ART) to prevent mother-to-child transmission (PMTCT). Studies suggest HIV-exposed uninfected (HEU) children face higher mortality than HIV-unexposed children, but most evidence relates to the pre-ART era, breastfeeding of limited duration, and considerable maternal mortality. Maternal ART and prolonged breastfeeding while on ART may improve survival, although this has not been reliably quantified.

**Methods.** Individual data on 19 219 HEU children from 21 PMTCT trials/cohorts undertaken from 1995 to 2015 in Africa and Asia were pooled to estimate the association between 24-month mortality and maternal/infant factors, using random-effects Cox proportional hazards models. Adjusted attributable fractions of risks computed using the predict function in the R package “frailtypack” were used to estimate the relative contribution of risk factors to overall mortality.

**Results.** Cumulative incidence of death was 5.5% (95% confidence interval, 5.1–5.9) by age 24 months. Low birth weight (LBW <2500 g, adjusted hazard ratio (aHR, 2.9), no breastfeeding (aHR, 2.5), and maternal death (aHR, 11.1) were significantly associated with increased mortality. Maternal ART (aHR, 0.5) was significantly associated with lower mortality. At the population level, LBW accounted for 16.2% of 24-month mortality, never breastfeeding for 10.8%, mother not receiving ART for 45.6%, and maternal death for 4.3%; combined, these factors explained 63.6% of deaths by age 24 months.

**Conclusions.** Survival of HEU children could be substantially improved if public health practices provided all HIV-infected mothers with ART and supported optimal infant feeding and care for LBW neonates.

**Keywords.** HIV-exposed uninfected; children, infants; mortality; Asia; Africa.

Received 3 July 2017; editorial decision 8 December 2017; accepted 19 December 2017; published online December 21, 2017.

ªOn behalf of the Kesho Bora Study Team.

Correspondence: S. Arikawa, University of Bordeaux, Inserm, Bordeaux Population Health Research Center, 146 Rue Léo Saignat, 33076 Bordeaux Cedex, France (shino.arikawa@u-bordeaux.fr).

**Clinical Infectious Diseases®** 2018;66(11):1668–77

© The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. DOI: 10.1093/cid/cix1102

Antiretroviral therapy (ART) to prevent mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV) has dramatically reduced the number of HIV-infected infants [1, 2]. As more women living with HIV survive and become pregnant, the number of HIV-exposed uninfected (HEU) children continues to increase [3]. Several studies have shown that HEU children may experience worse health outcomes than

<footnote n="1">¹University of Bordeaux, Inserm, Bordeaux Population Health Research Center, Team IDLIC, France; ²Department of Maternal, Newborn, Child and Adolescent Health, World Health Organization, Geneva, Switzerland; ³Institut de recherche pour le développement UMI 174-PHPT, Marseille, France; ⁴Faculty of Associated Medical Sciences, Chiang Mai University, Thailand; ⁵Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; ⁶Department of International Health, Center for Global Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland; ⁷Women's Health and Fertility Branch, Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, and ⁸Emory University School of Medicine and Eastern Virginia Medical School, Atlanta, Georgia; ⁹Division of Infectious Diseases, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill; ¹⁰Sigma3 Services SARL, Nyon, Switzerland; ¹¹Maternal Adolescent and Child Health, University of the Witwatersrand, Johannesburg. ¹²South African Medical Research Council, Cape Town, and ¹³Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa; ¹⁴Gertrude H. Sergievsky Center, College of Physicians and Surgeons, and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York; ¹⁵Inserm, Centre de recherche Inserm U1027, Université Paul Sabatier Toulouse 3, France; ¹⁶Center for Clinical Global Health Education, Johns Hopkins University, Baltimore, Maryland; ¹⁷Makerere University-Johns Hopkins University Research Collaboration/MU-JHU CARE LTD, Kampala, Uganda; ¹⁸Division of HIV, Infectious Diseases and Global Medicine, University of California San Francisco, and Zuckerberg San Francisco General Hospital; ¹⁹University Paris-Diderot, Assitance Publique Hôpitaux de Paris, ²⁰Institut National d'Etudes Démographiques (Ined), Paris, and ²¹University of Bordeaux, Inserm, Bordeaux Population Health Research Center, Team Biostatistics, France; ²²Institute for Developmental Science and Global Health Research Institute, Faculty of Medicine, University of Southampton, United Kingdom</footnote>
HIV-unexposed uninfected (HUU) children in the same setting [4–10], although this has not been confirmed elsewhere [11–14]. Most evidence relates to the era before widespread use of ART for PMTCT and for treatment, when increased mortality in HEU children was associated with poor maternal health and lack of prolonged breastfeeding. Maternal ART for life and prolonged breastfeeding with the protection of ART could ameliorate such negative associations [15, 16], but this has not yet been reliably quantified.

By pooling available individual data on HEU children from clinical trials and observational studies, from both the pre- and post-ART era, we assessed mortality risk in HEU children in Africa and Asia and associated factors. We also estimated the relative importance of identified risk factors in mediating poor outcomes among HEU children.

## METHODS

In a recent systematic review [17], we electronically searched 2 bibliographic databases, PubMed and Scopus, for articles published from 2004 to 2015 using the following keywords: HIV, Mortality, and Child or Infant, without restrictions on type or region of study, limited to English and French. Titles and abstracts were assessed; retained articles were subject to full-text reviews with identification of additional references. Additionally, we identified PMTCT trials with potential data on mortality in HEU children. A total of 29 studies were identified, and their principal investigators were contacted. One declined participation [18], 5 were unable to share data [5, 19–22] and 2 did not meet the inclusion criteria [23, 24], leaving 21 studies for the pooled 24-month mortality analysis: 16 from sub-Saharan Africa [4, 8, 25–38] and 5 from Asia [39–42]. Of these, 17 were randomized trials and 4 were observational studies conducted at different times (Supplementary Table S1), with varying sample sizes and follow-up durations (Table 1).

Maternal antiretroviral exposure was categorized as none; single/double peripartum antiretrovirals for PMTCT; 3-drug ART for PMTCT given antenatally and postnatally until cessation of breastfeeding when breastfeeding or until delivery when exclusively formula-fed; or 3-drug ART for life, prescribed beyond breastfeeding cessation per World Health Organization (WHO) HIV treatment and prevention recommendations [43, 44]. Mothers with missing information on antiretroviral use (n = 44) were assumed to have followed the relevant study protocol [28, 35] and thus categorized into the single/double antiretroviral PMTCT. The final HIV status of each child was defined by study-specific criteria. In our analyses, each child contributed from birth to 24 months of age, with right-censoring in case of death, end of study follow-up, and loss to follow-up. We restricted analyses to HEU children with information on breastfeeding and excluded 457 children with unknown infant feeding status. Mortality rates per 100 child-years of follow-up were estimated by maternal and child characteristics. We used

the Kaplan-Meier method to estimate survival curves and the log-rank test to test for differences between groups.

Associations between 24-month mortality and the following factors were assessed: residence (rural vs urban/peri-urban), sex, low birth weight (LBW; <2500 g), breastfeeding (ever/never), maternal education (none/primary vs above), maternal age at delivery (5-year categories), maternal antiretroviral exposure (fixed), and maternal vital status (time-dependent). Children known to have initiated breastfeeding but with unknown weaning date (n = 1032) were considered to have been breastfed from birth to either age 6 months per WHO feeding guidance at the time [45], study exit date, or date of mother's death, whichever occurred first. We used random-effects Cox proportional hazards models to estimate the association between 24-month mortality and potential risk factors, accounting for heterogeneity between studies. The final multivariable model included region (Africa vs Asia) as a fixed effect and adjusted for maternal antenatal CD4 cell count (categorical) because CD4 counts and ART eligibility varied widely between studies. Data from different sites in Kesho Bora [31] and HIVNET024 [30] were treated separately. Missing data were included as a separate category to maintain sample size. We used a stepwise-descending approach for selection of variables in multivariable models, which included variables that were statistically significant in univariate analyses (at a *P* value < .1, except for maternal antiretroviral exposure, which was maintained in the model independent of statistical significance). In the final model, statistical significance was reached when the *P* value was < .05. We also analyzed the association between weaning and survival among breastfed children only (n = 13418), with breastfeeding cessation defined in a time-varying manner.

We assessed the combined effects of breastfeeding and maternal 3-drug ART (for PMTCT or for life) on mortality, classifying observation time for each HEU child into 4 categories defined by child being breastfed (yes/no) and mother being on 3-drug ART (yes/no), with breastfeeding and ART variables being time dependent. When the date of ART end was unknown, ART was assumed to have continued until the weaning date or 6 months post-partum [45], whichever came first. The association between 24-month mortality and breastfeeding/maternal 3-drug ART was assessed in multivariable analyses using Cox proportional hazards models and allowing for heterogeneity between studies/trials and adjusting for region as fixed effect and maternal antenatal CD4 cell count and birth weight (<2500 g) as categorical variables.

Finally, to investigate the relative contribution of risk factors to overall 24-month mortality in HEU children, we estimated the adjusted attributable fractions (aAFs) of risks based on our final multivariable model [46, 47]. The AF for a given factor was the number of deaths attributable to the factor divided by the total number of deaths in our population if the prevalence of other factors remained at the same level. To do this, we first
<table><caption>Table 1. Characteristics of the Mothers and Children in Included in the Studies/Trials (N = 19219)</caption><thead><tr><th rowspan="2">Trial/Study</th><th rowspan="2">No. of Children</th><th colspan="3">Follow-up Duration (days)</th><th colspan="2">Birth Weight (&lt;2500 g)</th><th colspan="2">Ever Breastfed</th><th colspan="2">Breastfeeding Duration (days)</th><th colspan="3">Antenatal Maternal CD4 (cells/mm³)</th><th colspan="2">Maternal Death</th><th colspan="2">Child Death</th><th colspan="2">Child Age at Death (days)</th></tr><tr><th>n</th><th>Median</th><th>Q1</th><th>Q3</th><th>n</th><th>%</th><th>n</th><th>%</th><th>Median</th><th>Q1</th><th>Q3</th><th>Median</th><th>Q1</th><th>Q3</th><th>n</th><th>%</th><th>n</th><th>%</th><th>Median</th><th>Q1</th><th>Q3</th></tr></thead><tbody><tr><td>BAN</td><td>2250</td><td>336</td><td>254</td><td>338</td><td>174</td><td>7.7</td><td>2250</td><td>100</td><td>169</td><td>167</td><td>196</td><td>439</td><td>330</td><td>582</td><td>9</td><td>0.4</td><td>56</td><td>2.5</td><td>190</td><td>61</td><td>283</td></tr><tr><td>Ditrame(ANRSa)</td><td>312</td><td>551</td><td>385</td><td>641</td><td>43</td><td>13.8</td><td>306</td><td>98.1</td><td>283</td><td>188</td><td>505</td><td>596</td><td>403</td><td>781</td><td>18</td><td>4.5</td><td>32</td><td>10.3</td><td>77</td><td>4</td><td>130</td></tr><tr><td>Ditrame(ANRSb)</td><td>90</td><td>546</td><td>284</td><td>604</td><td>15</td><td>16.7</td><td>89</td><td>98.9</td><td>342</td><td>237</td><td>484</td><td>576</td><td>420</td><td>809</td><td>9</td><td>8.7</td><td>16</td><td>178</td><td>71</td><td>36</td><td>176</td></tr><tr><td>Ditrame Plus</td><td>688</td><td>730</td><td>538</td><td>734</td><td>83</td><td>12.1</td><td>395</td><td>57.4</td><td>124</td><td>96</td><td>200</td><td>411</td><td>258</td><td>569</td><td>13</td><td>1.7</td><td>53</td><td>7.7</td><td>2</td><td>1</td><td>79</td></tr><tr><td>HIV/GLOB/SWEN</td><td>575</td><td>546</td><td>541</td><td>549</td><td>62</td><td>10.8</td><td>574</td><td>99.9</td><td>105</td><td>77</td><td>150</td><td>436</td><td>292</td><td>596</td><td>2</td><td>0.3</td><td>21</td><td>3.7</td><td>70</td><td>15</td><td>207</td></tr><tr><td>Uganda</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>HIVNET024</td><td>1457</td><td>377</td><td>340</td><td>401</td><td>139</td><td>9.5</td><td>1457</td><td>100</td><td>284</td><td>108</td><td>366</td><td>366</td><td>240</td><td>523</td><td>40</td><td>2.4</td><td>67</td><td>4.6</td><td>173</td><td>116</td><td>273</td></tr><tr><td>Good Start</td><td>259</td><td>252</td><td>252</td><td>252</td><td>31</td><td>12.0</td><td>259</td><td>52.8</td><td>252</td><td>252</td><td>252</td><td></td><td></td><td></td><td>13</td><td>2.7</td><td>8</td><td>3.1</td><td>74</td><td>56</td><td>123</td></tr><tr><td>Kesho Bora</td><td>965</td><td>561</td><td>543</td><td>730</td><td>90</td><td>9.3</td><td>723</td><td>74.9</td><td>156</td><td>80</td><td>192</td><td>341</td><td>258</td><td>435</td><td>10</td><td>1.0</td><td>66</td><td>6.8</td><td>126</td><td>29</td><td>213</td></tr><tr><td>Mashi</td><td>1102</td><td>1096</td><td>730</td><td>1461</td><td>80</td><td>7.3</td><td>533</td><td>48.3</td><td>176</td><td>119</td><td>182</td><td>370</td><td>244</td><td>517</td><td>31</td><td>2.8</td><td>83</td><td>75</td><td>75</td><td>12</td><td>224</td></tr><tr><td>Mma Bana</td><td>702</td><td>731</td><td>730</td><td>733</td><td>102</td><td>14.5</td><td>680</td><td>96.9</td><td>178</td><td>141</td><td>181</td><td>347</td><td>231</td><td>484</td><td>11</td><td>1.6</td><td>35</td><td>5.0</td><td>151</td><td>6</td><td>243</td></tr><tr><td>PEP</td><td>779</td><td>210</td><td>153</td><td>246</td><td>128</td><td>16.4</td><td>405</td><td>52.0</td><td>81</td><td>38</td><td>123</td><td>477</td><td>323</td><td>664</td><td>11</td><td>1.4</td><td>18</td><td>2.3</td><td>109</td><td>71</td><td>138</td></tr><tr><td>PHPT-1</td><td>1283</td><td>551</td><td>546</td><td>558</td><td>126</td><td>9.8</td><td>0</td><td>0</td><td></td><td></td><td></td><td>362</td><td>240</td><td>510</td><td>49</td><td>3.8</td><td>3</td><td>0.2</td><td>185</td><td>182</td><td>548</td></tr><tr><td>PHPT-2</td><td>1805</td><td>368</td><td>365</td><td>373</td><td>172</td><td>9.5</td><td>0</td><td>0</td><td></td><td></td><td></td><td>376</td><td>247</td><td>531</td><td>6</td><td>0.3</td><td>4</td><td>0.2</td><td>283</td><td>180</td><td>289</td></tr><tr><td>PHPT-5 1st</td><td>407</td><td>731</td><td>553</td><td>737</td><td>51</td><td>12.5</td><td>0</td><td>0</td><td></td><td></td><td></td><td>454</td><td>366</td><td>569</td><td>0</td><td>0</td><td>0</td><td>0</td><td></td><td></td><td></td></tr><tr><td>PHPT-5 2nd</td><td>310</td><td>189</td><td>184</td><td>207</td><td>62</td><td>20.0</td><td>0</td><td>0</td><td></td><td></td><td></td><td>361</td><td>250</td><td>489</td><td>0</td><td>0</td><td>1</td><td>0.3</td><td>156</td><td>156</td><td>156</td></tr><tr><td>PROMOTE2</td><td>361</td><td>404</td><td>310</td><td>408</td><td>69</td><td>19.1</td><td>357</td><td>98.9</td><td>365</td><td>280</td><td>392</td><td>377</td><td>280</td><td>506</td><td>9</td><td>2.5</td><td>9</td><td>2.5</td><td>138</td><td>22</td><td>238</td></tr><tr><td>SWEN</td><td>628</td><td>366</td><td>364</td><td>368</td><td>177</td><td>28.2</td><td>627</td><td>99.8</td><td>101</td><td>98</td><td>182</td><td>472</td><td>324</td><td>667</td><td>8</td><td>1.3</td><td>14</td><td>2.2</td><td>46</td><td>27</td><td>188</td></tr><tr><td>Tshipidi</td><td>429</td><td>735</td><td>731</td><td>774</td><td>60</td><td>14.0</td><td>34</td><td>7.93</td><td>181</td><td>44</td><td>184</td><td>426</td><td>320</td><td>577</td><td>7</td><td>1.6</td><td>22</td><td>5.1</td><td>23</td><td>2</td><td>166</td></tr><tr><td>VTS</td><td>936</td><td>703</td><td>485</td><td>779</td><td>101</td><td>10.8</td><td>854</td><td>91.2</td><td>224</td><td>177</td><td>281</td><td>479</td><td>342</td><td>642</td><td>44</td><td>4.7</td><td>39</td><td>4.2</td><td>125</td><td>54</td><td>261</td></tr><tr><td>ZEBS</td><td>763</td><td>729</td><td>368</td><td>730</td><td>82</td><td>10.8</td><td>763</td><td>100</td><td>182</td><td>126</td><td>487</td><td>361</td><td>237</td><td>498</td><td>47</td><td>6.2</td><td>93</td><td>12.2</td><td>245</td><td>129</td><td>394</td></tr><tr><td>Zvitambo</td><td>3118</td><td>464</td><td>365</td><td>729</td><td>474</td><td>15.2</td><td>3113</td><td>99.8</td><td>456</td><td>365</td><td>553</td><td>423</td><td>279</td><td>593</td><td>134</td><td>4.3</td><td>245</td><td>7.9</td><td>82</td><td>38</td><td>201</td></tr></tbody></table>
obtained the total number of deaths at a given time by summing
the individual predicted probabilities of survival for each child
based on the predict function in the R package "frailtypack"
[48], then we subtracted this number from the total popula-
tion to derive the number of deaths. To estimate the number of
deaths attributable to the exposure of interest, we computed the
number of deaths in the population as if it was not exposed to
the factor while exposures to other risk factors were unchanged.
Nonexposure was simulated by setting all children to the ref-
erence category. For example, for deaths associated with LBW,
all children were classified into the category of having birth
weight great than 2500 g. The number of deaths attributable to
a specific factor was the difference between the total number of
deaths calculated previously and the number of deaths in the
unexposed population. We estimated the aAFs of the identi-
fied risk factors at 6, 12, and 24 months of age and computed
95% confidence intervals (CIs) using bootstrapping [49]. All
statistical analyses were performed using SAS version 9.3 (SAS
Institute, Cary, North Carolina). For the estimates of AF, we
used the R package's "frailtypack" [48] and "boot" [49] using R
version 3.3.2 (R Development Core Team, 2004).

RESULTS

A total of 19219 HEU children were part of the analyses (Figure 1). Maternal/child baseline characteristics are shown in Table 2. Median child follow-up was 404 days (interquartile range [IQR], 336–712). More than 75% of children were born in sub-Saharan Africa, mostly Southern Africa; nearly 70% were born prior to 2005. Most children were ever breastfed (69.8%) for a median 181 days (IQR, 126–365). Maternal antiretroviral exposure varied across studies (Supplementary Table S2), reflecting the timing of the study and prevailing ART and PMTCT recommendations [44]. Overall, 23% of mothers

received no antiretrovirals, 61% received mono/dual peripar-
tum antiretrovirals for PMTCT, 12% received 3-drug ART for
PMTCT, and only 4% were on ART for life. Median antenatal
CD4 count was 405 cells/mm³ (IQR, 280–563); 58% of moth-
ers had a CD4 count >350 cells/mm³ at the first antenatal visit.
Median antenatal CD4 count in women who received ART for
life was low at 214 cells/mm³ (IQR, 147–361). Median dur-
ation of ART was 178 (IQR, 152–196) and 443 (IQR, 371–730)
days for 3-drug ART for PMTCT and ART for life, respectively.
Information on maternal viral load was missing for 16%; among
those with available information, median antenatal viral load
was 4.0 log₁₀ copies/mL (IQR, 3.3–4.6).

HEU Child Mortality

Cumulative incidence of death was 2.1% (394/18012; 95% CI, 1.9–2.3), 3.1% (575/17176; 95% CI, 2.9–3.4), 4.5% (797/12153; 95% CI, 4.2–4.8), and 5.5% (884/4245; 95% CI, 5.1–5.9) by age 3, 6, 12, and 24 months, respectively. Median age at death was 111 days (IQR, 37–244). Mortality varied from 0% in PHPT-5 1st [42] to 17.8% in Ditrame-ANRSb [26] (Table 1). Stratified by geographical region (Figure 2), 24-month survival probability was significantly higher in Asia than in Africa (*P* < .0001). Of the 300 children whose mothers died, 17% (n = 51) did not survive after mother’s death. Child mortality declined with increasing age at the time of mother’s death: 52% if mother died within 1 month of delivery, 36% if she died between 1 and 3 months, 20% between 3 and 6 months, 6% between 6 and 12 months, and 4% between 12 and 24 months. Mortality was highest among children with mothers not being on any antiretrovirals (6.1/100 child-years), with mortality in single/dual antiretrovirals for PMTCT, 3.1/100; 3-drug ART for PMTCT, 2.7/100; and ART for life, 3.4/100 child-years. Of note, one- third of the single/dual antiretrovirals for PMTCT and the 3-drug ART for PMTCT groups, respectively, were comprised of mothers of children in

<figure><img src="image_2.png" /><figcaption>**Figure 1.** Flow chart of the children included in the pooled analyses. Abbreviations: HIV, human immunodeficiency virus; ID, identification.</figcaption></figure>
<table><caption>Table 2. Baseline Characteristics of the Study Population (N = 19219)</caption><thead><tr><th colspan="3">Child Characteristics</th></tr></thead><tbody><tr><td colspan="3"><strong>Follow-up duration (days) (median, IQR)</strong></td></tr><tr><td></td><td>404</td><td>336-712</td></tr><tr><td colspan="3"><strong>Region (N, %)</strong></td></tr><tr><td>East Africa</td><td>1620</td><td>8.4</td></tr><tr><td>Southern Africa</td><td>11 769</td><td>61.2</td></tr><tr><td>West Africa</td><td>1397</td><td>7.3</td></tr><tr><td>South Asia</td><td>628</td><td>3.3</td></tr><tr><td>Southeast Asia</td><td>3805</td><td>19.8</td></tr><tr><td colspan="3"><strong>Residence (N, %)</strong></td></tr><tr><td>Rural</td><td>1868</td><td>9.8</td></tr><tr><td>Urban/Peri-urban</td><td>17 351</td><td>90.2</td></tr><tr><td colspan="3"><strong>Access to piped water at home (N, %)</strong></td></tr><tr><td>Yes</td><td>6182</td><td>32.2</td></tr><tr><td>No</td><td>4268</td><td>22.2</td></tr><tr><td>Unknown</td><td>8769</td><td>45.6</td></tr><tr><td colspan="3"><strong>Years of birth (N, %)<sup>a</sup></strong></td></tr><tr><td>1995-1999</td><td>4659</td><td>24.2</td></tr><tr><td>2000-2004</td><td>8419</td><td>43.8</td></tr><tr><td>2005-2009</td><td>4852</td><td>25.3</td></tr><tr><td>2010-2014</td><td>1289</td><td>6.7</td></tr><tr><td colspan="3"><strong>Sex (N, %)</strong></td></tr><tr><td>Male</td><td>9839</td><td>51.2</td></tr><tr><td>Female</td><td>9376</td><td>48.8</td></tr><tr><td>Unknown</td><td>4</td><td>0.0</td></tr><tr><td colspan="3"><strong>Birth weight (N, %)</strong></td></tr><tr><td>≥2500 g</td><td>16 653</td><td>86.6</td></tr><tr><td>&lt;2500 g</td><td>2321</td><td>12.1</td></tr><tr><td>Unknown</td><td>245</td><td>1.3</td></tr><tr><td colspan="3"><strong>Child ever breastfed (N, %)</strong></td></tr><tr><td>Yes</td><td>13 418</td><td>69.8</td></tr><tr><td>No</td><td>5801</td><td>30.2</td></tr><tr><td colspan="3"><strong>Breastfeeding duration (days) (median, IQR) (N = 13 418)</strong></td></tr><tr><td></td><td>181</td><td>126-365</td></tr><tr><td colspan="3"><strong>Maternal characteristics</strong></td></tr><tr><td colspan="3"><strong>Education (N, %)</strong></td></tr><tr><td>None/Primary</td><td>8676</td><td>45.1</td></tr><tr><td>Secondary or above</td><td>9688</td><td>50.4</td></tr><tr><td>Unknown</td><td>855</td><td>4.5</td></tr><tr><td colspan="3"><strong>Maternal age at delivery (years) (N, %)</strong></td></tr><tr><td>15-20</td><td>2074</td><td>10.8</td></tr><tr><td>21-25</td><td>6159</td><td>32.1</td></tr><tr><td>26-30</td><td>5175</td><td>26.9</td></tr><tr><td>31-35</td><td>2545</td><td>13.2</td></tr><tr><td>&gt;35</td><td>1011</td><td>5.3</td></tr><tr><td>Unknown</td><td>2255</td><td>11.7</td></tr><tr><td colspan="3"><strong>Maternal ARVs/ART (N, %)</strong></td></tr><tr><td>No ARVs</td><td>4392</td><td>22.8</td></tr><tr><td>Single or double ARVs for PMTCT</td><td>11 805</td><td>61.4</td></tr><tr><td>3-drug ART for PMTCT</td><td>2248</td><td>11.7</td></tr><tr><td>ART for life</td><td>774</td><td>4.0</td></tr><tr><td colspan="3"><strong>Antenatal CD4 count above 350 cells/mm<sup>3</sup> (N, %)</strong></td></tr><tr><td>Yes</td><td>11 129</td><td>57.9</td></tr><tr><td>No</td><td>7010</td><td>36.5</td></tr><tr><td>Unknown</td><td>1080</td><td>5.6</td></tr><tr><td colspan="3"><strong>Antenatal CD4 count (median, IQR) (N = 18 139)</strong></td></tr><tr><td></td><td>405</td><td>280-563</td></tr></tbody></table>

<table><caption>Table 2. Continued</caption><thead><tr><th colspan="3">Child Characteristics</th></tr></thead><tbody><tr><td colspan="3"><strong>Antenatal viral load above 5 log10 copies/mL (N, %)</strong></td></tr><tr><td>Yes</td><td>2097</td><td>10.9</td></tr><tr><td>No</td><td>14 037</td><td>73.0</td></tr><tr><td>Unknown</td><td>3085</td><td>16.1</td></tr><tr><td colspan="3"><strong>Antenatal viral load (log<sub>10</sub> copies/mL) (median, IQR) (N = 16 134)</strong></td></tr><tr><td>4.0</td><td>3.3-4.6</td><td></td></tr></tbody></table>

Abbreviations: ART, antiretroviral therapy; ARV, antiretroviral; IQR, interquartile range; PMTCT, prevent mother-to-child transmission.

PHPT trials where child deaths were rarely observed, which might explain lower mortality rates in these 2 groups.

### Association With Maternal/Child Characteristics

Univariably, LBW children were at 3-fold risk of dying as were never-breastfed children (Table 3). Children whose mother had died were 16 times as likely to die compared to children whose mothers survived; maternal antiretroviral exposure was associated with reduced child mortality, but this did not reach statistical significance. Adjusting for region, maternal antenatal CD4 count, maternal antiretroviral exposure, and maternal vital status, LBW and never breastfeeding remained significantly associated with increased mortality (Table 3). The association between maternal ART for life and reduced child mortality became statistically significant (adjusted hazard ratio [aHR], 0.5; 95% CI, 0.3–0.9) after adjusting for maternal CD4 count (HR, 0.72 in univariate analysis, declining to 0.54 after adjusting for maternal CD4 count only). Associations between mortality and the other antiretroviral categories did not reach statistical significance (single/dual antiretrovirals: aHR, 0.78; 95% CI, 0.50–1.22 and 3-drug ART for PMTCT: aHR, 0.66; 95% CI, 0.39–1.13). Children whose mother had died remained at a substantially increased risk of death (aHR, 11.1).

Additional analyses, including ever-breastfed children only (n = 13418) and treating breastfeeding cessation as a time-dependent variable, showed mortality risk to be significantly increased after breastfeeding cessation. Adjusting for region, birth weight, maternal CD4 count, and maternal antiretroviral exposure, breastfeeding cessation was associated with a 12.5-fold (95% CI, 10.3–15.3) risk of death. In this model, children whose mothers received 3-drug ART (both PMTCT and for life) were at significantly lower risk of death (aHR, 0.51; 95% CI, 0.30–0.85 for 3-drug ART for PMTCT and aHR, 0.45; 95% CI, 0.22–0.92 for ART for life) than children whose mothers did not receive antiretrovirals (ARVs).

### Sensitivity Analyses

To investigate the sensitivity of our assumption on 44 women with no information on ARV exposure, we ran the analyses and

<footnote>ªInformation on the date of birth was not available in HIVNET024 and ZEBS. As the enrollment into these studies took place in 2001–2003 and 2001–2004, respectively, these children were classified into the 2000–2004 category.</footnote>
<figure><img src="image_3.png" /><figcaption>**Figure 2.** Kaplan-Meier estimates of 24-month survival from birth by geographical region.</figcaption></figure>

excluded these women; the aHRs were virtually unchanged. Further, 2 additional analyses were carried out to verify the effects of the inclusion of 1032 children with no information on weaning date and our assumption on their breastfeeding cessation at 6 months. After excluding these children, in the model with breastfeeding treated as a fixed effect, all aHRs were comparable to results shown in Table 3 (aHR, 3.0; 95% CI, 2.3–3.9 vs aHR, 2.5; 95% CI, 2.0–3.2). When breastfeeding was treated as a time-dependent variable, the risk related to breastfeeding cessation increased slightly but remained comparable to results presented in Table 3 (aHR, 16.9; 95% CI, 13.5–21.1 vs aHR, 13.1; 95% CI, 10.7–16.0).

### Combined Effects of Maternal ART and Breastfeeding

Mortality by age 24 months differed significantly by breastfeeding and maternal 3-drug ART status at a given time (*P* < .0001; Table 4). Compared to not currently breastfed children with mothers not receiving 3-drug ART (category A in Table 4), mortality risk in not currently breastfed children with mothers receiving 3-drug ART (category B) was significantly reduced (HR, 0.6). In the absence of maternal 3-drug ART, currently breastfed children (category C) were significantly less likely to die (HR, 0.07). Currently breastfed children whose mothers were receiving 3-drug ART (category D) had the lowest mortality risk (HR, 0.04).

### Adjusted Attributable Fractions of Risks

To investigate the impact of LBW, never breastfeeding, mother not on 3-drug ART for life, and maternal death, we estimated the aAFs of risks based on the parameter estimates obtained from our final model (Table 3). Mother not receiving 3-drug ART for life accounted for 45.6% (95% CI, 19.1–63.9) of child deaths by age 24 months. LBW accounted for an estimated 16.2% of child deaths by age 24 months, never breastfeeding for 10.8%, and

maternal death for 4.3%. Combined, these 4 factors explained 63.6% (95% CI, 45.7–76.6) of deaths by age 24 months. The aAFs of risks at 6 and 12 months related to these 4 factors did not significantly differ from those at 24 months (Table 5).

## DISCUSSION

Using data from 21 studies/trials undertaken between 1995 and 2015 in Africa and Asia, our findings suggest that where mothers are alive, on ART for life, and breastfeed their infants, 24-month mortality in HEU children is substantially reduced.

As reported previously [50–52], LBW, prevalent in 12% of these HEU children, was a major risk factor for mortality. However, the negative consequences of LBW and non-breast-feeding may be even greater in settings outside the context of well-resourced research studies. Almost half of HEU deaths occurred in the first 3 months of life and two-thirds before age 6 months, highlighting the importance of intervening program-matically in this early period.

The survival of mothers living with HIV had a major effect on the survival of HEU children; this association has also been reported among HUU children [53]. In our analyses, the death of a mother shortly after delivery was most hazardous for the survival of her HEU child.

Our results suggest that the risk of mortality in HEU children is reduced when mothers are on ART either until breastfeeding cessation or for life. Mother's initiation and continuation of ART likely improves her own health, which in turn increases the chances of child survival through better breastfeeding practices, reduced exposure to comorbidities, improved mother's care capacity, and other unmeasured benefits at the household level.
<table><caption>Table 3. Factors Associated With Mortality Through 24 Months of Age in Human Immunodeficiency Virus–Exposed Uninfected Children (n = 19219)</caption><thead><tr><th rowspan="2">Factor</th><th rowspan="2">Total Number of Children (n = 19219)</th><th rowspan="2">Total Number of Deaths (n = 884)</th><th rowspan="2">Mortality Rate per 100 Child-Years of Follow-up</th><th colspan="3">Univariate Model</th><th colspan="3">Multivariable Model</th></tr><tr><th>Hazard Ratio</th><th>95% CI</th><th>P Value</th><th>Adjusted Hazard Ratio</th><th>95% CI</th><th>P Value</th></tr></thead><tbody><tr><td><strong>Region</strong></td><td></td><td></td><td></td><td></td><td></td><td>&lt;.0001</td><td></td><td></td><td>&lt;.0001</td></tr><tr><td>Africa</td><td>14786</td><td>862</td><td>4.6</td><td>Ref.</td><td></td><td></td><td>Ref.</td><td></td><td></td></tr><tr><td>Asia</td><td>4433</td><td>22</td><td>0.4</td><td>0.08</td><td>0.04</td><td>0.17</td><td>0.05</td><td>0.02</td><td>0.11</td></tr><tr><td><strong>Residence</strong></td><td></td><td></td><td></td><td></td><td></td><td>0.22</td><td></td><td></td><td></td></tr><tr><td>Rural</td><td>1868</td><td>101</td><td>3.5</td><td>Ref.</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Urban/Peri-urban</td><td>17351</td><td>783</td><td>3.7</td><td>0.84</td><td>0.64</td><td>1.11</td><td></td><td></td><td></td></tr><tr><td><strong>Sex<sup>a</sup></strong></td><td></td><td></td><td></td><td></td><td></td><td>0.28</td><td></td><td></td><td></td></tr><tr><td>Male</td><td>9839</td><td>467</td><td>3.8</td><td>Ref.</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Female</td><td>9376</td><td>417</td><td>3.6</td><td>0.93</td><td>0.82</td><td>1.06</td><td></td><td></td><td></td></tr><tr><td><strong>Birth weight</strong></td><td></td><td></td><td></td><td></td><td></td><td>&lt;.0001</td><td></td><td></td><td>&lt;.0001</td></tr><tr><td>≥2500 g</td><td>16553</td><td>613</td><td>2.9</td><td>Ref.</td><td></td><td></td><td>Ref.</td><td></td><td></td></tr><tr><td>&lt;2500 g</td><td>2321</td><td>246</td><td>9.1</td><td>3.09</td><td>2.66</td><td>3.58</td><td>2.92</td><td>2.51</td><td>3.39</td></tr><tr><td>Unknown</td><td>245</td><td>25</td><td>8.1</td><td>2.21</td><td>1.47</td><td>3.33</td><td>2.40</td><td>1.60</td><td>3.61</td></tr><tr><td><strong>Breastfeeding</strong></td><td></td><td></td><td></td><td></td><td></td><td>&lt;.0001</td><td></td><td></td><td>&lt;.0001</td></tr><tr><td>Ever breastfed</td><td>13418</td><td>700</td><td>4.2</td><td>Ref.</td><td></td><td></td><td>Ref.</td><td></td><td></td></tr><tr><td>Never breastfed</td><td>5801</td><td>184</td><td>2.5</td><td>2.76</td><td>2.14</td><td>3.57</td><td>2.48</td><td>1.95</td><td>3.16</td></tr><tr><td><strong>Maternal age at delivery (years)</strong></td><td></td><td></td><td></td><td></td><td></td><td>0.42</td><td></td><td></td><td></td></tr><tr><td>15-20</td><td>2074</td><td>103</td><td>4.4</td><td>Ref.</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>21-25</td><td>6159</td><td>276</td><td>3.9</td><td>0.91</td><td>0.73</td><td>1.15</td><td></td><td></td><td></td></tr><tr><td>26-30</td><td>5175</td><td>231</td><td>3.8</td><td>0.91</td><td>0.72</td><td>1.16</td><td></td><td></td><td></td></tr><tr><td>31-35</td><td>2545</td><td>99</td><td>3.2</td><td>0.80</td><td>0.61</td><td>1.06</td><td></td><td></td><td></td></tr><tr><td>&gt;35</td><td>1011</td><td>35</td><td>2.8</td><td>0.73</td><td>0.50</td><td>1.08</td><td></td><td></td><td></td></tr><tr><td>Unknown</td><td>2255</td><td>140</td><td>3.5</td><td>1.25</td><td>0.43</td><td>3.68</td><td></td><td></td><td></td></tr><tr><td><strong>Maternal education</strong></td><td></td><td></td><td></td><td></td><td></td><td>0.03</td><td></td><td></td><td></td></tr><tr><td>None/Primary</td><td>8676</td><td>389</td><td>3.7</td><td>Ref.</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Secondary or above</td><td>9688</td><td>477</td><td>3.7</td><td>0.88</td><td>0.76</td><td>1.03</td><td></td><td></td><td></td></tr><tr><td>Unknown</td><td>855</td><td>18</td><td>3.3</td><td>0.23</td><td>0.05</td><td>1.05</td><td></td><td></td><td></td></tr><tr><td><strong>Maternal CD4 count (cells/mm<sup>3</sup>)</strong></td><td></td><td></td><td></td><td></td><td></td><td>&lt;.0001</td><td></td><td></td><td>&lt;.0001</td></tr><tr><td>≥350</td><td>11129</td><td>417</td><td>3.0</td><td>Ref.</td><td></td><td></td><td>Ref.</td><td></td><td></td></tr><tr><td>&lt;350</td><td>7010</td><td>403</td><td>4.6</td><td>1.58</td><td>1.38</td><td>1.82</td><td>1.43</td><td>1.24</td><td>1.66</td></tr><tr><td>Unknown</td><td>1080</td><td>64</td><td>5.6</td><td>1.55</td><td>1.16</td><td>2.07</td><td>1.49</td><td>1.12</td><td>1.99</td></tr><tr><td><strong>Maternal antiretroviral category</strong></td><td></td><td></td><td></td><td></td><td></td><td>0.28</td><td></td><td></td><td>0.13</td></tr><tr><td>No ARVs</td><td>4392</td><td>305</td><td>6.0</td><td>Ref.</td><td></td><td></td><td>Ref.</td><td></td><td></td></tr><tr><td>Single or double ARV for PMTCT</td><td>11805</td><td>469</td><td>3.1</td><td>0.67</td><td>0.42</td><td>1.07</td><td>0.78</td><td>0.50</td><td>1.22</td></tr><tr><td>3-drug ART for PMTCT</td><td>2248</td><td>73</td><td>2.7</td><td>0.61</td><td>0.34</td><td>1.07</td><td>0.66</td><td>0.39</td><td>1.13</td></tr><tr><td>ART for life</td><td>774</td><td>37</td><td>3.4</td><td>0.72</td><td>0.38</td><td>1.37</td><td>0.51</td><td>0.28</td><td>0.94</td></tr><tr><td><strong>Maternal vital status (time-dependent)</strong></td><td></td><td></td><td></td><td></td><td></td><td>&lt;.0001</td><td></td><td></td><td>&lt;.0001</td></tr><tr><td>Alive</td><td></td><td>833</td><td>3.5</td><td>Ref.</td><td></td><td></td><td>Ref.</td><td></td><td></td></tr><tr><td>Dead</td><td></td><td>51</td><td>35.7</td><td>15.9</td><td>11.9</td><td>21.2</td><td>11.08</td><td>8.25</td><td>14.89</td></tr></tbody></table>

Variable trial/study was included in all models as random effects.

Abbreviations: ART, antiretroviral therapy; ARV, antiretroviral; CI, confidence interval; HR, hazard ratio; PMTCT, prevent mother-to-child transmission.

The estimated AFs differed from the aHRs. This indicates that the impact at the population level, which reflects prevalence of risk factors, differs from that at the individual level. The CI

around the AF estimate of mother not receiving 3-drug ART for life was particularly wide, and caution is required in interpreting this result. Our estimated AFs show that 36% of HEU

<footnote><sup>a</sup>Excluding n = 4 with no information on sex.</footnote>

<footnote><sup>b</sup>Not applicable for time-dependent variables.</footnote>
<table><caption>Table 4. Multivariate Analysis on the Effects of Breastfeeding and Maternal 3-Drug Antiretroviral Therapy on Child Mortality (n = 24 186 child-years)</caption><thead><tr><th>Category</th><th>Child Currently Breastfed<sup>a</sup></th><th>Mother Being on 3-Drug Antiretroviral Therapy<sup>a</sup></th><th>Number of Child-Years</th><th>Number of Deaths</th><th>Adjusted Hazard Ratio<sup>b</sup></th><th>95% Confidence Interval</th><th>P Value</th></tr></thead><tbody><tr><td>A</td><td>No</td><td>No</td><td>14 119</td><td>552</td><td>Ref.</td><td></td><td>&lt;.0001</td></tr><tr><td>B</td><td>No</td><td>Yes</td><td>1027</td><td>44</td><td>0.63</td><td>0.45 0.87</td><td></td></tr><tr><td>C</td><td>Yes</td><td>No</td><td>7874</td><td>269</td><td>0.08</td><td>0.06 0.09</td><td></td></tr><tr><td>D</td><td>Yes</td><td>Yes</td><td>1166</td><td>19</td><td>0.04</td><td>0.03 0.07</td><td></td></tr></tbody></table>

child mortality at age 24 months could not be accounted for by the 4 risk factors identified and highlighted that HEU children are also at risk of death from other common causes of child mortality. The lack of contemporaneous mortality data from HUU children meant that we were unable to categorically comment whether HEU children are at any greater mortality risk if these 4 risk factors are fully addressed.

Although the analyses include a large number of HEU children from diverse settings, interpretation of findings is hindered by lack of detail on potentially important variables including gestational age, neonatal care practices (early initiation and type of breastfeeding), and household exposure to opportunistic infections (such as tuberculosis). These factors may account for much of the remaining 36% mortality.

Relatively few women were on ART for life, and studies generally followed earlier WHO guidelines on HIV and infant feeding, recommending breastfeeding for about 6 months only. Although we confirm the associations between reduced mortality risk and maternal ART for life and breastfeeding, our data does not allow us to fully capture the complex associations between different factors that influence a child's survival outcome. The women on ART in our study are a highly select population, and we cannot comment on the extent to which such reductions are facilitated by study-specific factors and whether such associations would be equally observed in women on ART

in standard-of-care settings. Further, due to lack of data, we were unable to allow for cotrimoxazole prophylaxis and childhood immunization, which are used to prevent infectious morbidity in young children.

We were also unable to differentiate small-for-gestational age from premature infants in those with LBW. About 11% of all infants in Eastern and Southern Africa are born with LBW; in Southeast Asia it is around 28% [54]. LBW has been associated with HIV infection in pregnant women in sub-Saharan Africa and with the protease inhibitor class of ART during pregnancy [55–57]. While the primary drivers for LBW may vary by region and HIV exposure, the relationship between LBW and mortality in both HEU and HUU children is clear and strong and has immediate programmatic implications.

The combination of 3-drug ART was introduced in about the middle of the timespan covered by the studies included; ART eligibility criteria varied over time as did inclusion for trials. Although we could not allow for these trends, these factors could have introduced selection bias. Each study had its own criteria for eligibility, including CD4 counts. Data included in our analyses were heterogeneous in terms of feeding and duration of follow-up, which limits our ability to generalize the results beyond these studies. Finally, exclusion of 457 children whose breastfeeding status was unknown might have led to underestimation of mortality rates as almost 29% (132/457) of

<table><caption>Table 5. Estimated Adjusted Attributable Fractions and 95% Confidence Intervals of Risk Factors for Mortality in Human Immunodeficiency Virus–Exposed Uninfected Children at Different Time Points</caption><thead><tr><th rowspan="3">Expected Number of Deaths Given the Distribution at 6, 12, and 24 Months</th><th colspan="3">0–6 Months</th><th colspan="3">0–12 Months</th><th colspan="3">0–24 Months</th></tr><tr><th colspan="3">755</th><th colspan="3">1054</th><th colspan="3">1444</th></tr><tr><th>Number of Deaths Attributable to the Risk Factor(s)</th><th>aAF (%)</th><th>95% CI</th><th>Number of Deaths Attributable to the Risk Factor(s)</th><th>aAF (%)</th><th>95% CI</th><th>Number of Deaths Attributable to the Risk Factor(s)</th><th>aAF (%)</th><th>95% CI</th></tr></thead><tbody><tr><td>Mother not receiving 3-drug antiretroviral therapy for life</td><td>342</td><td>47.9</td><td>20.0–65.8</td><td>466</td><td>46.9</td><td>15.6–64.9</td><td>620</td><td>45.6</td><td>19.1–63.9</td></tr><tr><td>Low birth weight</td><td>140</td><td>18.5</td><td>15.1–21.9</td><td>184</td><td>17.4</td><td>14.2–20.6</td><td>234</td><td>16.2</td><td>13.1–19.2</td></tr><tr><td>Breastfeeding never initiated</td><td>88</td><td>11.7</td><td>5.2–19.6</td><td>119</td><td>11.3</td><td>5.0–18.9</td><td>157</td><td>10.8</td><td>4.9–17.9</td></tr><tr><td>Mother not being alive</td><td>44</td><td>5.9</td><td>3.1–13.5</td><td>53</td><td>5.1</td><td>2.7–11.5</td><td>62</td><td>4.3</td><td>2.3–9.3</td></tr><tr><td>All 4 factors above</td><td>486</td><td>66.2</td><td>48.6–78.4</td><td>666</td><td>65.0</td><td>47.2–77.7</td><td>891</td><td>63.6</td><td>45.7–76.6</td></tr></tbody></table>

Abbreviations: aAF; adjusted attributable fraction; CI, confidence interval.

<footnote><sup>a</sup>Time-dependent variables.</footnote>

<footnote><sup>b</sup>Variable trial/study was included as random effects. Also adjusted for region, maternal antenatal CD4 count, and birth weight.</footnote>
these children died before age 12 months; 105 died before age 1 month, 17 between age 1 and 3 months, and 10 died thereafter.

We show substantial regional differences in 24-month mor-
tality, which deserves further investigation, as do the issues
surrounding breastfeeding. Explaining the missing fraction of
HIV-related and other external mortality risk factors requires
prospectively collected data from both HEU and HUU popu-
lations. It remains unclear whether HEU infants and children

are immunologically impaired at a clinically significant
level or whether increased exposure to opportunistic infec-
tions because of living in HIV-affected households would ex-
plain the missing fraction. Perhaps the most germane question
is whether increasing rollout of lifelong ART among women
living with HIV and fully supporting optimal infant feeding
practices will mitigate the patterns of risks identified in these
historical cohorts. With more and more women living with HIV
being initiated on ART, understanding the interactions between
fetal HIV and ART exposure, the effects of prematurity or
small-for-gestational age on mortality, and the effects of other
long-term outcomes including early child development, infec-
tious morbidity, and the risk of noncommunicable diseases will
be increasingly important.

CONCLUSIONS

Our findings show that not-breastfeeding and LBW were associ-
ated with considerable mortality risk and suggest that maternal
ART, initiated before or during pregnancy, may substantially re-
duce child mortality in the first 2 years of life. With increasing
numbers of HIV-infected pregnant women being initiated on
ART, this would provide hope for reducing overall child mortality
in settings of high HIV prevalence. The importance of delivering
effective integrated care so that women living with HIV are not
only initiated on ART but are also linked with other essential ele-
ments of maternal and child healthcare is clear. Eliminating pedi-
atric HIV and improving the survival, health, and development
of HEU children should not be separate from improving the
well-being of mothers and children not affected by HIV, and our
metric of success needs to evolve to “HIV-free survival and devel-
opment.” While integrated programs and coordinated research
and monitoring are unquestionably possible, continued global
investment in these responses is perhaps the greatest challenge.

**Supplementary Data**

Supplementary materials are available at *Clinical Infectious Diseases* online.
Consisting of data provided by the authors to benefit the reader, the posted
materials are not copyedited and are the sole responsibility of the authors,
so questions or comments should be addressed to the corresponding author.

Notes

**Author contributions.** R. B., M. L. N., and N. R. initiated and set the objectives of the collaboration, defined the statistical analysis plans, and substantially contributed to the writing of the manuscript. S. A. undertook the literature review, managed the data pooling, participated in the

definition of the statistical analysis plan, performed statistical analysis, and
wrote the first draft of the paper. M. R. and P. J. substantially contributed to
the statistical analysis. G. J., J. H., T. F., G. G., L. K., R. S., V. L., S. L., R. C. B.,
T. D., and S. L. C. critically reviewed the manuscript and substantially con-
tributed to the interpretation of the results. All other coauthors reviewed
the manuscript.

**Acknowledgments.** BAN: Charles van der Horst, Denise Jamieson; Ditrame-ANRSa: Christiane Welfens-Ekra, Philippe Msellati; Ditrame-ANRSb: Nicolas Meda, Philippe Van de Perre; Ditrame Plus: Marguerite Timité-Konan, Clarisse Bosse; Good Start: Mickey Chopra, Debra Jackson, Vundli Ramokolo, Ameena Goga; HIVIGLOB: J. Brooks Jackson, Laura A. Guay, Philippa Musoke, Mary Glenn Fowler, Michael C. Mubiru; PEP: Mike Urban (University of Stellenbosch); PHPT: Marc Lallemant, principal investigator of the PHPT clinical trials, all PHPT coinvestigators, the PHPT staff who helped collect and manage the data, and Nicolas Salvadori for the preparation of the data-set of the PHPT studies. PROMOTE2: Diane Havlir, Theodore Ruel. SWEN: Amita Gupta, Jayagowri Sasty, Harjot K. Singh; ZEBS: The late Moses Sinkala (Lusaka District Health Management Team), Chipepo Kankasa (University Teaching Hospital), Donald M. Thea (Boston University), Grace M. Aldrovandi (University of California–Los Angeles).

**Disclaimer.** The World Health Organization (WHO) had no role in the study design, data collection, data analysis, or interpretation of data. The findings and conclusions in this paper are those of the authors and do not necessarily represent the official position of WHO or the Centers for Disease Control and Prevention.

**Funding.** This work was funded by the WHO.

**Potential conflicts of interest.** All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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