Cotrimoxazole Prophylaxis and Risk of Severe Anemia or Severe Neutropenia in HAART-Exposed, HIV-Uninfected Infants

Background: Prophylactic cotrimoxazole is recommended for infants born to HIV-infected mothers. However, cotrimoxazole may increase the risk of severe anemia or neutropenia. Methods: We compared the proportion of HIV-exposed uninfected (HIV-EU) infants experiencing incident severe anemia (and separately, severe neutropenia) between a prospective cohort receiving prophylactic cotrimoxazole from 1 to 6 months vs. infants from two prior trials who did not receive cotrimoxazole. Infants were from rural and urban communities in southern Botswana. Results: A total of 1705 HIV-EU infants were included. Among these 645 (37.8%) were fed with iron-supplemented formula from birth. Severe anemia developed in 87 (5.1%) infants, and severe neutropenia in 164 (9.6%) infants. In an analysis stratified by infant feeding method, there were no significant differences in the risk of severe anemia by prophylactic cotrimoxazole exposure–risk difference, −0.69% (95% confidence interval [CI] −2.1 to 0.76%). Findings were similar in multivariable analysis, adjusted odds ratio (aOR) 0.35 (95% CI 0.07 to 1.65). There were also no significant differences observed for severe neutropenia by cotrimoxazole exposure, risk difference 2.0% (95% CI −1.3 to 5.2%) and aOR 0.80 (95% CI 0.33 to 1.93). Conclusions: Severe anemia and severe neutropenia were infrequent among HIV-exposed uninfected infants receiving cotrimoxazole from 1–6 months of age. Concerns regarding hematologic toxicity should not limit the use of prophylactic cotrimoxazole in HIV-exposed uninfected infants. ClinicalTrials.gov Registration Numbers NCT01086878 (http://clinicaltrials.gov/show/NCT01086878), NCT00197587 (http://clinicaltrials.gov/show/NCT00197587), and NCT00270296 (http://clinicaltrials.gov/show/NCT00270296)

Severe infant anemia and severe neutropenia by prophylactic cotrimoxazole exposure.

<p>Analysis restricted to severe anemia or neutropenia (grade 3 or 4) detected at scheduled measurements at 3 and/or 6 months of age in HIV-exposed uninfected infants in the CTX, Mashi, and Mma Bana cohorts.</p><p>Note: 95% CI, 95% confidence interval.</p>a<p>Mantel-Haenszel methodology.</p>b<p>Exact Cochran-Mantel-Haenszel.</p

Factors associated with severe anemia and severe neutropenia among HIV-exposed, uninfected infants.

<p>Prophylactic cotrimoxazole, maternal antenatal HAART use, and infant feeding method are included in the multivariable model, as are other significant factors from the univariate analysis.</p><p>OR, odds ratio; aOR, adjusted odds ratio; CI, confidence interval; HAART, highly-active antiretroviral therapy.</p>a<p>Wald chi-square.</p>b<p>To avoid confounding effect of infant feeding method, univariate estimate for effect of cotrimoxazole is restricted to formula-fed infants. Multivariable analysis includes both formula-fed and breastfed infants.</p>c<p>A modest but significant interaction was noted between feeding method and maternal HAART with increased risk of severe neutropenia associated with breastfeeding from a mother receiving HAART. However, in multivariable analysis this interaction was no longer significant.</p

Cohort characteristics of HIV-exposed uninfected infants alive through 30 days of age.

<p>Note: CTX, cotrimoxazole; IQR, interquartile range.</p

Schematic of infant exposures in study cohorts.

<p>ZDV, zidovudine; supp., supplementation; CTX, cotrimoxazole; HAART, highly-active antiretroviral therapy; mo., month. ^aHAART became available through a national program in October 2002, subsequently women in Mashi trial with CD4≤200 cells/ µL were offered HAART.^bInfants in the Mma Bana trial received 1 month of ZDV and breastfed infants in the Mashi trial received 6 months of ZDV.^cNineteen mothers (9.1%) in CTX cohort received non-ZDV-containing HAART.</p

Enrollment and follow-up of study infants.

<p>HIV-uninfected infants in the Mashi and Mma Bana trials did not receive cotrimoxazole prophylaxis and serve as a comparison group to the new cohort (CTX) that received cotrimoxazole prophylaxis. CTX, cotrimoxazole; 1 mo., one month; FF, formula-fed; BF, breastfed.</p