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Effects of concurrent exposure to antiretrovirals and cotrimoxazole prophylaxis among HIV-exposed, uninfected infants

Ewing, Alexander C.a; King, Caroline C.a; Wiener, Jeffrey B.a; Chasela, Charles S.b; Hudgens, Michael G.c; Kamwendo, Debbied; Tegha, Geraldd; Hosseinipour, Mina C.c; Jamieson, Denise J.a; Van der Horst, Charlesc; Kourtis, Athena P.a

doi: 10.1097/QAD.0000000000001641
CLINICAL SCIENCE
Free

Background: Given the potential of cotrimoxazole preventive therapy (CPT) to prevent bacterial and malarial infections in HIV-exposed, uninfected (HEU) infants, it is important to evaluate the effects of its concurrent use with antiretroviral agents that have overlapping toxicity profiles.

Methods: We used data from the Breastfeeding, Antiretrovirals, and Nutrition study (2004–2010) to evaluate the association of CPT and antiretrovirals with hematologic measures (hemoglobin, neutrophil, and alanine aminotransferase levels) from 6 to 48 weeks of age in 2006 HEU infants in Lilongwe, Malawi. Hazards of severe outcomes (anemia, neutropenia, and elevated alanine aminotransferase), as defined by the National Institutes of Health, were compared using Cox regression models, according to time-varying CPT (implemented June 2006), antiretroviral treatment arm (maternal triple antiretroviral, infant nevirapine, or none during 6 months of breastfeeding), and their interaction. The effects of these treatments on hemoglobin, neutrophil, and alanine aminotransferase levels were assessed using linear mixed models.

Results: In Cox models, CPT was associated with an increase in severe neutropenia [hazard ratio 1.97 (1.01, 3.86)] and a decrease in severe anemia (hazard ratio 0.65 (0.48, 0.88)]. Interactions between CPT and antiretroviral treatment were not significant. By 36 weeks, there was a significant association of CPT with increased hemoglobin levels regardless of antiretroviral drug exposure.

Conclusions: In addition to expected associations with increased hazard of severe neutropenia and decreased neutrophil count, CPT was associated with reduced hazard of severe anemia and higher infant blood hemoglobin. This provides further support for CPT use in HEU infants in malaria-endemic resource-limited settings where anemia is prevalent.

aCenters for Disease Control and Prevention, Atlanta, Georgia, USA

bDepartment of Epidemiology and Biostatistics, School of Public Health, University of Witwatersrand, Johannesburg, South Africa

cUniversity of North Carolina, Chapel Hill, North Carolina, USA

dUNC Project, Lilongwe, Malawi.

Correspondence to Alexander C. Ewing, MPH, Centers for Disease Control and Prevention, 4770 Buford Highway, MS F74, Chamblee, GA, 30341-3717, USA. E-mail: Yhy4@cdc.gov

Received 12 April, 2017

Revised 15 August, 2017

Accepted 3 September, 2017

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Introduction

In settings where pneumonia, diarrhea, and malnutrition are major causes of infant mortality, breastfeeding for 12 months combined with antiretroviral and cotrimoxazole preventive therapy (CPT) offers infants of HIV-infected mothers the greatest chance for HIV-free survival and is recommended by the WHO [1]. Clinical trials showing the efficacy of antiretroviral regimens for reduced risk of HIV transmission to breastfeeding infants and those showing the efficacy of CPT against opportunistic infections [2–4] have independently shown good overall safety. However, both maternal and infant antiretroviral and cotrimoxazole prophylaxis have been independently associated with reports of hematologic toxicities, including neutropenia and anemia [5–16]. These conditions, particularly severe anemia, are major causes of morbidity in Malawi and sub-Saharan Africa [17–20]. Given the similar hematologic side effects for some antiretroviral agents and cotrimoxazole, it is important to evaluate the impact of their concurrent use among HIV-exposed, uninfected (HEU) infants.

We conducted a secondary analysis of data from the Breastfeeding, Antiretrovirals, and Nutrition (BAN) – a clinical trial of 2369 mother–infant pairs randomized to 28 weeks of infant nevirapine, maternal antiretroviral drugs, or neither for the prevention of HIV transmission during breastfeeding (http://www.ClinicalTrials.gov number NCT00164736) [21]. During the study, new guidelines were issued for the use of CPT in HEU infants. We used data from this randomized antiretroviral design and mid-study implementation of CPT to evaluate the independent and concurrent effects of antiretroviral treatment and CPT on the risk of hematologic toxicities, including neutropenia, anemia, and elevated alanine transaminase (ALT) among HEU infants.

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Methods

Study enrollment, design, and procedures

Infants were enrolled in the BAN trial in Lilongwe, Malawi, between March 2004 and January 2010. The BAN study design and primary findings have been reported elsewhere and indicate that the use of either maternal triple antiretroviral prophylaxis or infant nevirapine for 28 weeks is effective in reducing HIV transmission during breastfeeding [21,22].

From March 2004 to February 2009, the study screened 3572 antiretroviral-naive, HIV-infected pregnant women attending antenatal clinics in Lilongwe, Malawi, and enrolled 2369 women who met antenatal and postnatal eligibility criteria. The antenatal criteria were age at least 14 years, no serious complications of pregnancy, no prior antiretroviral use, CD4+ cell count at least 250 cells/μl (≥200 cells/μl before 24 July 2006), hemoglobin at least 7 g/dl, plasma alanine aminotransferase (ALT) 2.5 times or less than the upper limit of normal, and planning to breastfeed. The postnatal criteria were infant birth weight at least 2000 g, no infant or maternal condition precluding study interventions, and the mother's acceptance of the perinatal antiretroviral regimen and treatment assignment within 36 h of delivery.

All mothers in labor and their newborn infants received a single dose of oral nevirapine, and 7 days of zidovudine 300 mg, and lamivudine 150 mg twice-daily, from the onset of labor for the mothers, and zidovudine (2 mg per kilogram of body weight) and lamivudine (4 mg per kilogram) twice daily for the infants. Mother–infant pairs who met eligibility criteria were randomly assigned to one of three antiretroviral intervention arms to be initiated at birth and continued for 28 weeks or until breastfeeding cessation, if earlier: infant nevirapine; maternal triple-drug antiretroviral regimen; or control (no mother or infant treatment). Using a standardized protocol derived from the WHO Breastfeeding Counseling Training Manual [23], all mothers were individually counseled to breastfeed exclusively for the first 24 weeks postpartum and then wean rapidly between 24 and 28 weeks. Due to overwhelming evidence of the benefit of the treatment arms, the Data Safety and Monitoring Board halted enrollment to the control arm after 668 mother–infant pairs had been assigned; participants in the control arm at that time were given the option of switching to the infant nevirapine or maternal antiretroviral arms for the remainder of the 28-week intervention period.

Mother–infant pairs were followed at 1, 2, 4, 6, 8, 12, 18, 21, 24, 28, 32, 36, 42, and 48 weeks postpartum, with the last pair completing follow-up in January 2010. Infants who tested HIV-positive were disenrolled and referred for care. A full blood count and ALT testing was done at birth, 2, 6, 12, 18, 24, 28, 36, and 48 weeks. Data capturing anthropometrics, vital signs, illnesses, and hospitalizations since the last visit, current symptoms, and physical examination findings were collected at all follow-up visits. Participants were advised to return to the clinic between visits to receive treatment if the woman or child was ill. Medical care was provided according to the standard of care at the study clinics, and participants were provided with insecticide-treated bed nets. Clinical and laboratory adverse events were identified at regular study visits, and interim sick visits were documented and graded according to toxicity tables from the National Institute of Allergy and Infectious Diseases Division of AIDS, 2004 version [24], with modifications to the neutropenia definitions implemented 10 May 2006 [21].

The BAN study was approved by the Malawi National Health Science Research Committee, and institutional review boards at the University of North Carolina at Chapel Hill and the US Centers for Disease Control and Prevention (CDC). All women provided written, informed consent for specimen storage and laboratory studies.

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Exposures

The 852 babies randomized to infant nevirapine received a daily dose of nevirapine that increased according to age, ranging from 10 mg daily in the first 2 weeks to 30 mg daily for weeks 19 through 28. The 849 mothers on the maternal antiretroviral arm received combivir (twice daily) and either nevirapine (200 mg) once daily for 14 days and twice daily through week 28 (n = 39), nelfinavir (1250 mg) twice daily through week 28 (n = 146), or lopinavir (400 mg) and ritonavir (100 mg) twice daily through week 28 (n = 664). These changes to the maternal antiretroviral regimen were made for reasons of safety, availability, and potency [21]. Data on antiretroviral adherence were collected at five follow-up visits, and mothers reported taking all their antiretroviral doses a mean of 89% of the time and giving all infant antiretroviral doses 94% of the time.

In accordance with the Malawi Ministry of Health and Population Guidelines and WHO guidelines on CPT [25,26], CPT was initiated in the BAN study for eligible women and infants on 13 June 2006. Cotrimoxazole was provided to all mothers with CD4+ below 500 cells/μl (480 mg twice daily) and to all infants (240 mg once daily) beginning at their first study visit after 6 weeks of age and taken through 36 weeks of age or until weaning occurred and HIV infection was ruled out.

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Outcomes

The outcomes studied in this analysis included severe forms of the following hematologic toxicities: anemia, neutropenia, and elevated ALT. For each outcome, severe toxicity was defined as exceeding the cut-point for grade 3 or higher on the 2014 version of the Division of AIDS toxicity tables [27]. Severe neutropenia was defined as below 600 cells/μl. Severe anemia was defined as hemoglobin levels below 8.5 g/dl for infants 56 days old or younger and below 9.5 g/dl for infants older than 56 days. Severe elevated ALT was defined as at least 5.0 times the upper limit of normal range. Additionally, hemoglobin concentrations, neutrophil counts, and ALT concentrations from full blood counts taken at scheduled study visits were used to assess hematologic changes longitudinally.

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Statistical methods

To examine the effects of CPT from 6 to 36 weeks postpartum, the 28-week postnatal antiretroviral intervention, and their interaction, this analysis was limited to HEU infants with at least one full blood count at the 6, 8, 12, 18, 21, 24, 28, 32, 36, 42, and 48-week postpartum study visits. This excluded 146 infants who were HIV-infected by 6 weeks of age, 17 HEU infants who died before 6 weeks of age, and 200 infants lost to follow-up or with missing laboratory data. The final sample included 2006 infants.

Descriptive analyses included calculation of frequencies and medians for all exposures, outcomes, and covariables. Categorical proportions were compared using chi-square tests and continuous variables were assessed using the Kruskal–Wallis test. To describe and illustrate the toxicity burdens suffered by the different groups, Cox proportional-hazards models, one per outcome, were used to assess the hazards of severe hematologic toxicities by time-dependent CPT status, antiretroviral arm, and their interaction, and did not include other covariates. The extended Kaplan–Meier method, as described by Snapinn et al.[28], was used to visualize the hazards assessed in the Cox models. According to the study protocol, infant follow-up was censored at death, maternal death, or loss to follow-up.

Linear mixed models were used to evaluate the effects of the time-dependent CPT exposure, antiretroviral arm, and their interaction on continuous longitudinal measurements of hemoglobin, neutrophils, and ALT. To determine whether the medication effects varied with infant age, interactions between week of age and CPT exposure were evaluated, and significant interaction terms were retained. Mixed models used an autoregressive covariance structure with a random effect for patient, and were adjusted for randomization to the maternal nutritional supplement arm, infant sex, birth weight, infant hematologic values measured at birth (neutrophil counts, hemoglobin, and ALT concentrations), maternal factors measured at birth (CD4+ cell count, BMI, and hemoglobin concentration), and rainy season (defined as November through March). In analyses considering time-varying CPT exposure, infants were considered exposed from the first visit at or later than 6 weeks postnatal until 48 weeks, meaning CPT status will vary only for individuals participating actively in follow-up when CPT is implemented. Study arm is modeled as an intent-to-treat variable. A sensitivity analysis was conducted, cutting off follow-up for all participants at the discontinuation of the control group (27 March 2008). Extended Kaplan–Meier plots were created using R 3.3.2; all other analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, North Carolina, USA).

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Results

Among the 2006 HEU infants, 553 were enrolled before and 1453 after study implementation of the new CPT guidelines (Table 1). There was a small, but significant difference in median maternal BMI, with higher values in the group enrolled after CPT implementation; there were no other differences in maternal characteristics or infant sex and birth weight according to either CPT implementation or antiretroviral treatment arm (Table 1). Prevalence of all three severe hematologic toxicities (anemia, neutropenia, and elevated ALT) was low at baseline.

Table 1

Table 1

Over the course of follow-up from 6 to 48 weeks of age, 10.5% of infants had at least one episode of severe anemia; by comparison, 3.5 and 0.8%, respectively, had severe neutropenia and elevated ALT.

Initial episodes of severe anemia were less frequent for infants exposed to CPT than for those not exposed to CPT, especially after 24 weeks of age (Fig. 1a), and CPT was associated with a decreased hazard of severe anemia [hazard ratio 0.65, 95% confidence interval (CI) 0.48–0.88] (Table 2). Compared to the control arm, the infant nevirapine arm had a significantly lower hazard of severe anemia (hazard ratio 0.68, 95% CI 0.48–0.96) (Table 2). Most initial episodes of severe anemia occurred later in follow-up (Fig. 1c).

Fig. 1

Fig. 1

Table 2

Table 2

Cox proportional-hazards models showed CPT exposure was associated with an increased hazard of severe neutropenia (hazard ratio 1.97, 95% CI 1.01–3.86) (Table 2). Unlike severe anemia, most initial episodes of severe neutropenia during follow-up occurred by 18 weeks of age (Fig. 1b), regardless of CPT exposure. Antiretroviral treatment arm was not significantly associated with severe neutropenia (Table 2, Fig. 1d).

Neither CPT exposure nor antiretroviral treatment arm assignment was associated with severe elevated ALT (Table 2). Models were also run with interaction terms between CPT exposure and weeks of age, and between CPT exposure and antiretroviral treatment arm for all of the outcomes studied, but none of the interactions tested showed statistical significance (data not shown).

Linear mixed models, used to analyze the longitudinal effects of CPT exposure on continuous hematologic outcomes, showed that CPT exposure was associated with increases in mean concentration of hemoglobin compared to infants not exposed to CPT, and that this association was modified by both antiretroviral treatment and infant age. The significant interactions in this model mean the beta coefficients presented for this model in Table 3 represent changes in mean hemoglobin concentration compared to CPT-unexposed infants in the control arm at 12 weeks of age. They indicate that the observed association of CPT with mean hemoglobin was greater for infants in the control arm and for older infants. Using the mixed-model coefficients, mean hemoglobin concentration was 0.18 g/dl (95% CI 0.03, 0.33) higher for those exposed to CPT in the control group at 12 weeks of age (Table 3). Mean hemoglobin concentration was higher in the maternal antiretroviral and infant nevirapine arms compared to the control arm when not exposed to CPT (increases of 0.25 and 0.18 g/dl, respectively, at 12 weeks of age), but these effects of antiretroviral treatment were diminished when exposed to CPT (decreases of 0.22 and 0.24 g/dl for maternal antiretroviral and infant nevirapine arms, respectively) due to the significant interaction terms.

Table 3

Table 3

Cotrimoxazole preventive therapy exposure was associated with a 191.8 cells/μl decrease in mean neutrophil count (95% CI −303.1, −80.6) in the control arm at 12 weeks of age; however, this decrease was reduced by 7.8 cells/μl for each additional week of age due to a significant interaction term. There was no significant interaction between CPT and study arm in the model with neutrophil count as the dependent variable.

Cotrimoxazole preventive therapy exposure was not associated with ALT levels (increase of 0.53 IU/l; 95% CI −0.68, 1.74) (Table 3).

Results of the sensitivity analysis where follow-up was cut off at the discontinuation of the control group yielded similar results to the main analysis (data not shown).

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Discussion

In this cohort of breastfed HEU infants followed until 48 weeks of life, severe anemia was relatively common, whereas severe neutropenia was rare. There was a significant decrease in severe anemia and a significant increase in severe neutropenia was associated with CPT. Longitudinal mixed models showed corresponding increases in hemoglobin levels and decreases in neutrophil counts associated with CPT exposure. Associations between CPT and hemoglobin levels increased with age, but were reduced by exposure to antiretroviral (either maternal antiretroviral or infant nevirapine). The reduction in neutrophil count associated with CPT exposure lessened with age.

A previous study on the effects of CPT on hematologic outcomes in HEU infants in Botswana showed that severe anemia and neutropenia were rare among HEU infants, and there was no association between CPT and either outcome [29]. Our research confirms the low frequency of severe neutropenia in HEU infants, whereas the difference in frequency of severe anemia may be attributable to the different populations studied. The BAN study took place in a region where malaria, a cause of anemia [30], is prevalent and all infants are breastfed, whereas the previous study took place in a nonmalarial region of Botswana and very few infants receiving CPT were breastfed. Nearly 50% of HEU infants in another study in Uganda and Zimbabwe (HPTN-046) who were taking CPT developed severe anemia and/or neutropenia [31]. However, the analysis focused on the effects of antiretrovirals in the studied population, and did not present results for severe anemia and severe neutropenia separately; also, because all participants were also exposed to CPT, the effects of each on the outcomes could not be determined.

Although there is evidence from studies in adults that the combination of CPT and zidovudine-containing antiretroviral treatment may cause hematologic toxicities [32], our analysis shows that for HEU infants in areas of high malarial prevalence, it is possible that CPT may reduce the occurrence of severe anemia. In a separate analysis of data from the BAN trial, it was shown that CPT was associated with a reduction in subclinical malaria, although it had no effect on clinical malaria [33]. Thus, CPT may cause a reduction in malaria-related anemia separate from the drug's direct effects on blood hemoglobin. Severe anemia in sub-Saharan Africa is associated with adverse clinical outcomes, including death [19,34,35], and the results of this analysis suggest that in populations with a high malaria prevalence, CPT has the potential to reduce the frequency of these outcomes among HIV-exposed infants.

The analysis did show an increase in severe neutropenia and a corresponding reduction in neutrophil counts associated with CPT. However, the effect on neutrophil count lessened with age, and the frequency of severe neutropenia was low even for those exposed to CPT. We did not find any association between CPT exposure and elevated ALT.

There was no overall difference in severe anemia or severe neutropenia according to antiretroviral treatment arm, although those infants receiving daily nevirapine did have a lower estimated hazard of severe anemia compared with the control arm. Likewise, in longitudinal mixed models, both maternal antiretroviral and infant nevirapine were associated with higher levels of hemoglobin in the absence of cotrimoxazole [36].

The study instructed mothers to wean rapidly after 28 weeks, and self-reported adherence to the breastfeeding schedule was high. Median breastfeeding duration was 169 days, and did not vary by study arm. Median breastfeeding duration was 172 days for infants born before CPT implementation and 169 days for those born after (Kruskal–Wallis test, P < 0.001). Current guidelines for HIV-infected women on antiretroviral therapy (ART) recommend breastfeeding until 12–24 months [36]. HIV-uninfected mothers in Malawi generally continue breastfeeding until about 24 months, which means that the infants will continue to be exposed to antiretrovirals and CPT. The reassuring findings of this study related to drug toxicities, combined with results from BAN and other studies showing increased morbidity and mortality in HIV-exposed infants after early weaning suggest that the benefits of continued breastfeeding should outweigh concerns related to these exposures.

Whereas a randomized controlled trial would be ideal to evaluate the hematologic effects of CPT in HEU infants in areas of high malaria prevalence, this is not possible or ethical following the release and implementation of CPT guidelines from the WHO and Malawi Ministry of Health. Thus, our analysis took advantage of the unplanned experiment caused by the BAN study's implementation of CPT in June 2006 by treating CPT as a time-varying exposure. To account for secular trends in participants’ environments and health that may have confounded the association between CPT and the studied outcomes, longitudinal mixed models included factors indicative of maternal and infant health before entry into the analysis cohort at 6 weeks of age, along with variables to account for seasonal changes. Despite our ability to control for these factors, there may have been changes over time in participants’ health unrelated to CPT that we could not account for.

Changes in the study protocol over time may have affected results. An increase in the minimum CD4+ cell count for enrollment eligibility, from less than 200 to less than 250, 6 months after CPT implementation and changes to the maternal antiretroviral regimen over time [21], may have led to the inclusion of healthier individuals later in the study, and changes in study population health unrelated to CPT. These changes should be at least partially addressed by the factors adjusted for in longitudinal mixed models, which included maternal CD4+ cell count. If changes to the maternal antiretroviral regimen improved outcomes at around the same time as CPT implementation and inflated the observed positive associations between CPT and hemoglobin levels, this effect should show up in the maternal antiretroviral arm. Instead, in linear mixed models, the positive association between CPT and hemoglobin levels was reduced in the maternal antiretroviral arm compared to the control arm, and associations between CPT and other outcomes did not differ according to study arm (Table 3). Likewise, the similarity of the results of the sensitivity analysis to the main analysis indicates that the observed effect of CPT was not due to the shift, later in the study, of participants to the two intervention arms. Rates of analysis-specific exclusions were nondifferential with respect to CPT implementation, so we do not have reason to expect bias to results. Most of the 146 HIV-related exclusions were due to in-utero infection (n = 119); postnatal before 6-week visit infections (n = 27) were more likely in the control group. If these excluded infants were more likely to suffer adverse study outcomes due to poor health, this could bias results related to the two antiretroviral arms towards significant associations, but the number involved is small and any effect is unlikely to be large. Exclusions due to loss to follow-up (LTFU) and infant deaths before the 6-week visit were nondifferential by study arm. The results of this analysis may only apply to populations similar to the one studied.

The findings of this analysis further support the use of daily CPT among HEU infants, especially in areas of high malaria prevalence. There has been concern about the potential for the combined use of CPT and antiretroviral treatment to cause hematologic toxicities. Whereas our data suggest that CPT may increase the hazard of severe neutropenia, the overall prevalence of this outcome remained low. The reduction in severe anemia associated with CPT is an additional benefit for HEU infants at increased risk for adverse health outcomes and mortality.

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Acknowledgements

Author contributions: A.P.K., C.S.C., C.vd.H., and D.J.J. designed the trial. C.S.C., D.K., G.T., M.C.H., and M.G.H. collected data. A.C.E., A.F., and C.C.K. analyzed data. A.C.E., A.P.K., C.C.K., J.B.W., C.vd.H., and D.J.J. interpreted data. A.C.E. wrote the manuscript. All authors reviewed versions of the report and contributed to the intellectual content of the article.

We are grateful to the BAN Study Team at University of North Carolina Chapel Hill, Centers for Disease Control and Prevention, Atlanta, and UNC Project in Lilongwe: Linda Adair, Yusuf Ahmed, Mounir Ait-Khaled, Sandra Albrecht, Shrikant Bangdiwala, Ronald Bayer, Margaret Bentley, Brian Bramson, Emily Bobrow, Nicola Boyle, Sal Butera, Charles Chasela, Charity Chavula, Joseph Chimerang’ambe, Maggie Chigwenembe, Maria Chikasema, Norah Chikhungu, David Chilongozi, Grace Chiudzu, Lenesi Chome, Anne Cole, Amanda Corbett, Amy Corneli, Nicole Davis, Anna Dow, Ann Duerr, Henry Eliya, Sascha Ellington, Joseph Eron, Sherry Farr, Yvonne Owens Ferguson, Susan Fiscus, Valerie Flax, Ali Fokar, Shannon Galvin, Laura Guay, Chad Heilig, Irving Hoffman, Elizabeth Hooten, Mina Hosseinipour, Michael Hudgens, Stacy Hurst, Lisa Hyde, Denise Jamieson, George Joaki (deceased), David Jones, Elizabeth Jordan-Bell, Zebrone Kacheche, Esmie Kamanga, Gift Kamanga, Coxcilly Kampani, Portia Kamthunzi, Deborah Kamwendo, Cecilia Kanyama, Angela Kashuba, Damson Kathyola, Dumbani Kayira, Peter Kazembe, Caroline C. King, Rodney Knight, Athena P. Kourtis, Robert Krysiak, Jacob Kumwenda, Hana Lee, Edde Loeliger, Dustin Long, Misheck Luhanga, Victor Madhlopa, Maganizo Majawa, Alice Maida, Cheryl Marcus, Francis Martinson, Navdeep Thoofer, Chrissie Matiki (deceased), Douglas Mayers, Isabel Mayuni, Marita McDonough, Joyce Meme, Ceppie Merry, Khama Mita, Chimwemwe Mkomawanthu, Gertrude Mndala, Ibrahim Mndala, Agnes Moses, Albans Msika, Wezi Msungama, Beatrice Mtimuni, Jane Muita, Noel Mumba, Bonface Musis, Charles Mwansambo, Gerald Mwapasa, Jacqueline Nkhoma, Megan Parker, Richard Pendame, Ellen Piwoz, Byron Raines, Zane Ramdas, John Rublein, Mairin Ryan, Ian Sanne, Christopher Sellers, Diane Shugars, Dorothy Sichali, Wendy Snowden, Alice Soko, Allison Spensley, Jean-Marc Steens, Gerald Tegha, Martin Tembo, Roshan Thomas, Hsiao-Chuan Tien, Beth Tohill, Charles van der Horst, Esther Waalberg, Elizabeth Widen, Jeffrey Wiener, Cathy Wilfert, Patricia Wiyo, Innocent Zgambo, Chifundo Zimba. Finally and most especially, all the women and infants that have agreed to participate in the study.

The Breastfeeding, Antiretrovirals, and Nutrition Study was supported by grants from the Prevention Research Centers Special Interest Project of the Centers for Disease Control and Prevention (SIP 13–01 U48-CCU409660-09, SIP 26-04 U48-DP000059-01, and SIP 22-09 U48-DP001944-01); the National Institute of Allergy and Infectious Diseases, the University of North Carolina Center for AIDS Research (P30-AI50410); the Carolina Population Center (R24 HD050924); the National Institutes of Health Fogarty International Programs [AIDS International Training and Research Program (D43 TW001039) and Scholars and Fellows Program (R24 TW007988); the American Recovery and Reinvestment Act]; and the Bill and Melinda Gates Foundation (Grant # OPP53107).

The antiretrovirals used in the BAN study were donated by Abbott Laboratories, GlaxoSmithKline, Boehringer Ingelheim, Roche Pharmaceuticals, and Bristol-Myers Squibb. The Call to Action PMTCT program was supported by the Elizabeth Glaser Pediatric AIDS Foundation, the United Nations Children's Fund, the World Food Program, the Malawi Ministry of Health and Population, Johnson & Johnson, and the U.S. Agency for International Development.

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

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Conflicts of interest

There are no conflicts of interest.

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References

1. Guidelines on Post-Exposure Prophylaxis for HIV and the Use of Co-Trimoxazole Prophylaxis for HIV-Related Infections Among Adults, Adolescents and Children: Recommendations for a Public Health Approach: December 2014 supplement to the 2013 consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Geneva: World Health Organization; 5 December 2014. https://www.ncbi.nlm.nih.gov/books/NBK298965/ [Accessed 21 February 2017].
2. Chintu C, Bhat GJ, Walker AS, Mulenga V, Sinyinza F, Lishimpi K, et al. Co-trimoxazole as prophylaxis against opportunistic infections in HIV-infected Zambian children (CHAP): a double-blind randomised placebo-controlled trial. Lancet 2004; 364:1865–1871.
3. Grimwade K, Swingler GH. Cotrimoxazole prophylaxis for opportunistic infections in children with HIV infection. Cochrane Database Syst Rev 2006. CD003508.
4. Mermin J, Lule J, Ekwaru JP, Malamba S, Downing R, Ransom R, et al. Effect of co-trimoxazole prophylaxis on morbidity, mortality, CD4-cell count, and viral load in HIV infection in rural Uganda. Lancet 2004; 364:1428–1434.
5. Anglaret X, Chêne G, Attia A, Toure S, Lafont S, Combe P, et al. Early chemoprophylaxis with trimethoprim-sulphamethoxazole for HIV-1-infected adults in Abidjan, Côte d’Ivoire: a randomised trial. Lancet 1999; 353:1463–1468.
6. Moore DAJ, Benepal T, Portsmouth S, Gill J, Gazzard BG. Etiology and natural history of neutropenia in human immunodeficiency virus disease: a prospective study. Clin Infect Dis 2001; 32:469–475.
7. Meynard JL, Guiguet M, Arsac S, Frottier J, Meyohas MC. Frequency and risk factors of infectious complications in neutropenic patients infected with HIV. AIDS 1997; 11:995–998.
8. Moyle G, Sawyer W, Law M, Amin J, Hill A. Changes in hematologic parameters and efficacy of thymidine analogue-based, highly active antiretroviral therapy: a meta-analysis of six prospective, randomized, comparative studies. Clin Ther 2004; 26:92–97.
9. Kovari H, Sabin CA, Ledergerber B, Ryom L, Reiss P, Law M, et al. Antiretroviral drugs and risk of chronic alanine aminotransferase elevation in human immunodeficiency virus (HIV)-monoinfected persons: The Data Collection on Adverse Events of Anti-HIV Drugs Study. Open Forum Infect Dis 2016; 3:ofw009.
10. 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. N Engl J Med 1994; 331:1173–1180.
11. Le Chenadec J, Mayaux MJ, Guihenneuc-Jouyaux C, Blanche S. Perinatal antiretroviral treatment and hematopoiesis in HIV-uninfected infants. AIDS 2003; 17:2053–2061.
12. Pacheco SE, McIntosh K, Lu M, Mofenson LM, Diaz C, Foca M, et al. Effect of perinatal antiretroviral drug exposure on hematologic values in HIV-uninfected children: An analysis of the women and infants transmission study. J Infect Dis 2006; 194:1089–1097.
13. Bunders MJ, Bekker V, Scherpbier HJ, Boer K, Godfried M, Kuijpers TW. Haematological parameters of HIV-1-uninfected infants born to HIV-1-infected mothers. Acta Paediatr 2005; 94:1571–1577.
14. Dryden-Peterson S, Shapiro RL, Hughes MD, Powis K, Ogwu A, Moffat C, et al. Increased risk of severe infant anemia after exposure to maternal HAART, Botswana. J Acquir Immune Defic Syndr 2011; 56:428–436.
15. Feiterna-Sperling C, Weizsaecker K, Buhrer C, Casteleyn S, Loui A, Schmitz T, et al. Hematologic effects of maternal antiretroviral therapy and transmission prophylaxis in HIV-1-exposed uninfected newborn infants. J Acquir Immune Defic Syndr 2007; 45:43–51.
16. Bae WH, Wester C, Smeaton LM, Shapiro RL, Lockman S, Onyait K, et al. Hematologic and hepatic toxicities associated with antenatal and postnatal exposure to maternal highly active antiretroviral therapy among infants. AIDS 2008; 22:1633–1640.
17. Koram KA, Owusu-Agyei S, Utz G, Binka FN, Baird JK, Hoffman SL, et al. Severe anemia in young children after high and low malaria transmission seasons in the Kassena-Nankana district of northern Ghana. Am J Trop Med Hygiene 2000; 62:670–674.
18. Newton CRJC, Warn PA, Winstanley PA, Peshu N, Snow RW, Pasvol G, et al. Severe anaemia in children living in a malaria endemic area of Kenya. Trop Med Int Health 1997; 2:165–178.
19. Calis JCJ, Phiri KS, Faragher EB, Brabin BJ, Bates I, Cuevas LE, et al. Severe anemia in Malawian children. N Engl J Med 2008; 358:888–899.
20. World Health Organization. The global prevalence of anaemia in 2011. Geneva, Switzerland: World Health Organization; 2015.
21. van der Horst C, Chasela C, Ahmed Y, Hoffman I, Hosseinipour M, Knight R, et al. Modifications of a large HIV prevention clinical trial to fit changing realities: a case study of the Breastfeeding, Antiretroviral, and Nutrition (BAN) protocol in Lilongwe, Malawi. Contemp Clin Trials 2009; 30:24–33.
22. Chasela CS, Hudgens MG, Jamieson DJ, Kayira D, Hosseinipour MC, Kourtis AP, et al. Maternal or infant antiretroviral drugs to reduce HIV-1 transmission. N Engl J Med 2010; 362:2271–2281.
23. World Health Organization, UNICEF. Breastfeeding counselling: a training course. http://www.who.int/maternal_child_adolescent/documents/who_cdr_93_3/en/ [Accessed 14 February 2017].
24. AIDS Clinical Trials Group. Division of AIDS table for grading the severity of adult and pediatric adverse events. Rockville, MD: National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS; 2004.
25. World Health Organization. Guidelines for cotrimoxazole prophylaxis for HIV-related infection among children, adolescents and adults in resource-limited settings. Recommendations for a public health approach. 2006; Geneva, Switzerland: WHO, http://http://www.who.int/hiv/pub/guidelines/ctx/en/http://www.who.int/hiv/pub/guidelines/ctx/en/ [Accessed 14 February 2017].
26. Government of Malawi. Cotrimoxazole preventive therapy for HIV-positive persons in Malawi. Lilongwe: Ministry of Health and Population; 2005.
27. Division of AIDS. Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0. U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases. 2014. Available from: http://rsc.tech-res.com/docs/default-source/safety/daids_ae_grading_table_v2_nov2014.pdf [Accessed 25 January 2017].
28. Snapinn SM, Jiang Q, Iglewicz B. Illustrating the impact of a time-varying covariate with an extended Kaplan-Meier estimator. Am Stat 2005; 59:301–307.
29. Dryden-Peterson S, Jayeoba O, Hughes MD, Jibril H, McIntosh K, Modise TA, et al. Cotrimoxazole prophylaxis and risk of severe anemia or severe neutropenia in HAART-exposed, HIV-uninfected infants. PLoS One 2013; 8:e74171.
30. Haldar K, Mohandas N. Malaria, erythrocytic infection, and anemia. Hematol Am Soc Hematol Educ Program 2009; 2009:87–93.
31. Aizire J, Fowler MG, Wang J, Shetty AK, Stranix-Chibanda L, Kamateeka M, et al. Extended prophylaxis with nevirapine and cotrimoxazole among HIV-exposed uninfected infants is well tolerated. AIDS (London, England) 2012; 26:325.
32. Moh R, Danel C, Sorho S, Sauvageot D, Anzian A, Minga A, et al. Haematological changes in adults receiving a zidovudine-containing HAART regimen in combination with cotrimoxazole in Cote d’Ivoire. Antivir Ther 2005; 10:615–624.
33. Davis NL, Barnett EJ, Miller WC, Dow A, Chasela CS, Hudgens MG, et al. Impact of daily cotrimoxazole on clinical malaria and asymptomatic parasitemias in HIV-exposed, uninfected infants. Clin Infect Dis 2015; 61:368–374.
34. Crawley J. Reducing the burden of anemia in infants and young children in malaria-endemic countries of Africa: from evidence to action. Am J Trop Med Hyg 2004; 71:25–34.
35. Redd SC, Wirima JJ, Steketee RW. Risk factors for anemia in young children in rural Malawi. Am J Trop Med Hygiene 1994; 51:170–174.
36. World Health Organization. Guideline updates on HIV and infant feeding: the duration of breastfeeding, and support from health services to improve feeding practices among mothers living with HIV. Geneva, Switzerland: World Health Organization; 2016.
Keywords:

anemia; antiretrovirals; BAN; breastfeeding; cotrimoxazole; hematologic toxicities; HIV-exposed uninfected; infants; malaria; neutropenia

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