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

ABSTRACT: 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.

SUBMITTER: Ewing AC

PROVIDER: S-EPMC6059368 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Ewing Alexander C AC King Caroline C CC Wiener Jeffrey B JB Chasela Charles S CS Hudgens Michael G MG Kamwendo Debbie D Tegha Gerald G Hosseinipour Mina C MC Jamieson Denise J DJ Van der Horst Charles C Kourtis Athena P AP

AIDS (London, England) 20171101 18

<h4>Background</h4>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.<h4>Methods</h4>We used data from the Breastfeeding, Antiretrovirals, and Nutrition study (2004-2010) to evaluate the association of CPT and antiretrovirals with hematologic measures (hemoglobin, neutrop ...[more]

PMID: 28926409

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Project description:IntroductionDespite declining risk of vertical HIV transmission, prophylactic cotrimoxazole (CTX) remains widely used to reduce morbidity and mortality in the event of HIV infection among exposed infants, with an inherent risk of conferring commensal antimicrobial resistance. Using data from a randomized, placebo-controlled trial of infant CTX prophylaxis, we sought to quantify emergence of antibiotic resistance.MethodsHIV-exposed uninfected infants enrolled in the Botswana Mpepu study were randomized to prophylactic CTX or placebo between 14 and 34 days of life and continued through 15 months. Stool samples were collected from a subset of participating infants at randomization, three, and six months, and stored at -70°C prior to culture. Specimens that grew Escherichia coli (E. coli) or Klebsiella species (Klebsiella spp.) underwent antibiotic susceptibility testing by Kirby Bauer method using CTX (CTX 1.25/23.75 μg) and Amoxicillin (10 μg) in Mueller Hinton agar. Fisher's exact testing was used to compare prevalence of resistance by randomization arm (CTX/placebo).Results and discussionA total of 381 stool samples from 220 infants were cultured: 118 at randomization, 151 at three months, and 112 at six-months. E. coli was isolated from 206 specimens and Klebsiella spp. from 138 specimens. Resistance to CTX was common in both E. coli and Klebsiella spp. at the randomization visit (52.2% and 37.7% respectively) and did not differ by study arm. E. Coli isolates from CTX recipients at three and six months had 94.9% and 84.2% CTX resistance, as compared with 51.4% and 57.5% CTX resistance in isolates from placebo recipients (p=0.01). Klebsiella spp. isolates from CTX recipients had 79.0% and 68.8% CTX resistance at three and six months, as compared with 19.1% and 14.3% in isolates from placebo recipients (p<0.01).ConclusionsHIV-exposed infants randomized to CTX prophylaxis had increased CTX-resistant commensal gastrointestinal bacteria compared with placebo recipients. Additional research is needed to determine the longer-term clinical, microbiologic, and public health consequences of antimicrobial resistance selected by infant CTX prophylaxis.

Project description:BackgroundProphylactic cotrimoxazole treatment is recommended in human immunodeficiency virus (HIV)-exposed, uninfected (HEU) infants, but the effects of this treatment on developing HEU infant gut microbiotas and resistomes are largely undefined.MethodsWe analyzed whole-metagenome sequencing data from 163 longitudinally collected stool samples from 63 HEU infants randomized to receive (n = 34; CTX-T) or to not receive (n = 29; CTX-N) prophylactic cotrimoxazole treatment. We generated taxonomic, functional pathway, and resistance gene profiles for each sample and compared microbiome signatures between the CTX-T and CTX-N infants.ResultsMetagenomic analysis did not reveal significant differences in taxonomic or functional pathway α-diversity between CTX-T and CTX-N infants. In contrast, resistance gene prevalence (P = .00719) and α-diversity (P = .0045) increased in CTX-T infants. These differences increased over time for both resistance gene prevalence measured by log-normalized abundance (4-month mean, 0.71 [95% confidence interval {CI}, .2-1.2] and 6-month mean, 0.85 [95% CI, .1-1.7]) and α-diversity (P = .0045). Unlike α-diversity, interindividual gut microbiome taxonomic (mean, -0.11 [95% CI, -.15 to -.077]), functional taxonomic (mean, -0.050 [95% CI, -.084 to -.017]), and resistance gene (mean, -0.13 [95% CI, -.17 to -.099]) β-diversity decreased in CTX-T infants compared with CTX-N infants. These results are consistent with persistent antibiotic selection pressure.ConclusionsCotrimoxazole prophylaxis in HEU infants decreased gut microbiome β-diversity and increased antibiotic resistance gene α-diversity and prevalence. Antibiotic resistance is a growing threat, especially in low- and middle-income countries where the higher perinatal HIV exposure rates result in cotrimoxazole prophylaxis. Understanding effects from current HEU infant antibiotic prophylaxis guidelines will inform guideline revisions and efforts to reduce increasing antibiotic resistance.

Dataset Information

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

Publications

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

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