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Sex Differences in Antiretroviral Therapy Initiation in Pediatric HIV Infection.

Mori M, Adland E, Paioni P, Swordy A, Mori L, Laker L, Muenchhoff M, Matthews PC, Tudor-Williams G, Lavandier N, van Zyl A, Hurst J, Walker BD, Ndung'u T, Prendergast A, Goulder P, Jooste P - PLoS ONE (2015)

Bottom Line: In a South African cohort of 2,101 HIV-infected children, we observed that absolute CD4+ count and CD4% were significantly higher in ART-naïve female, compared to age-matched male, HIV-infected children.Absolute CD4 count and CD4% were also significantly higher in HIV-uninfected female versus male neonates.The main sex difference in morbidity observed in children initiating ART above CD4 thresholds, above that of TB disease, was as a result of wasting and stunting observed in females with above-threshold CD4 counts (p=0.002).

View Article: PubMed Central - PubMed

Affiliation: Department of Paediatrics, University of Oxford, Oxford, United Kingdom.

ABSTRACT
The incidence and severity of infections in childhood is typically greater in males. The basis for these observed sex differences is not well understood, and potentially may facilitate novel approaches to reducing disease from a range of conditions. We here investigated sex differences in HIV-infected children in relation to antiretroviral therapy (ART) initiation and post-treatment outcome. In a South African cohort of 2,101 HIV-infected children, we observed that absolute CD4+ count and CD4% were significantly higher in ART-naïve female, compared to age-matched male, HIV-infected children. Absolute CD4 count and CD4% were also significantly higher in HIV-uninfected female versus male neonates. We next showed that significantly more male than female children were initiated on ART (47% female); and children not meeting criteria to start ART by >5 yrs were more frequently female (59%; p<0.001). Among ART-treated children, immune reconstitution of CD4 T-cells was more rapid and more complete in female children, even after adjustment for pre-ART absolute CD4 count or CD4% (p=0.011, p=0.030, respectively). However, while ART was initiated as a result of meeting CD4 criteria less often in females (45%), ART initiation as a result of clinical disease in children whose CD4 counts were above treatment thresholds occurred more often in females (57%, p<0.001). The main sex difference in morbidity observed in children initiating ART above CD4 thresholds, above that of TB disease, was as a result of wasting and stunting observed in females with above-threshold CD4 counts (p=0.002). These findings suggest the possibility that optimal treatment of HIV-infected children might incorporate differential CD4 treatment thresholds for ART initiation according to sex.

No MeSH data available.


Related in: MedlinePlus

Sex differences in immune reconstitution amongst the patients started treatment under the pre-2013 WHO guidelines.Sex differences by log rank test are shown as follows: A. Survival after ART initiation. B. CD4+ T cell percentage recovery (>35%) rate among the children who started ART aged 1–4 years old with CD4+ T cell <25%. C. Absolute CD4+ T cell count recovery (>750/ul) among children initiating ART aged ≥5 years old with absolute CD4+ T cell counts <350/ul.
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pone.0131591.g004: Sex differences in immune reconstitution amongst the patients started treatment under the pre-2013 WHO guidelines.Sex differences by log rank test are shown as follows: A. Survival after ART initiation. B. CD4+ T cell percentage recovery (>35%) rate among the children who started ART aged 1–4 years old with CD4+ T cell <25%. C. Absolute CD4+ T cell count recovery (>750/ul) among children initiating ART aged ≥5 years old with absolute CD4+ T cell counts <350/ul.

Mentions: We first analyzed treatment outcomes among the 1,244 children in whom ART was initiated based on WHO age criteria (<1yr) or CD4 criteria (described in the Methods). There was no sex difference in survival among these children (p = 0.42, Fig 4A), nor in the time to achieve viral suppression (<50 copies/ml, p = 0.26, not shown). However, even after adjustment for pre-ART CD4 counts or CD4% (see below), CD4+ T cell reconstitution to normal levels for age-matched uninfected children (defined as: CD4% ≥35% in children aged 1–4yr, or CD4 counts >750/ul in children aged ≥5yrs [13]) was more rapid and more complete in females (Fig 4B and 4C). Prior to ART initiation, the differences in CD4% and in CD4 counts did not reach statistical significance comparing male with female children (S2 Table), and, using the Cox hazard model, sex remained a significant covariate in CD4 reconstitution in favor of females in the 1–4yr group (adjusted hazard ratio 1.4, p = 0.030) and also in the ≥5yo group (adjusted hazard ratio 1.4, p = 0.011) (Table 2). In the two age groups of children studied (1–4yo and ≥5yo) in whom the CD4 ART initiation treatment criteria were, respectively, a CD4% <25%, and an absolute CD4 count of <350 cells/ul, recovery to a CD4% of ≥35% and ≥750 cells/ul, respectively, was independently associated with female sex and with pre-ART CD4% and absolute CD4 count, respectively. Pre-ART viral load in either case was not associated with speed of immune reconstitution.


Sex Differences in Antiretroviral Therapy Initiation in Pediatric HIV Infection.

Mori M, Adland E, Paioni P, Swordy A, Mori L, Laker L, Muenchhoff M, Matthews PC, Tudor-Williams G, Lavandier N, van Zyl A, Hurst J, Walker BD, Ndung'u T, Prendergast A, Goulder P, Jooste P - PLoS ONE (2015)

Sex differences in immune reconstitution amongst the patients started treatment under the pre-2013 WHO guidelines.Sex differences by log rank test are shown as follows: A. Survival after ART initiation. B. CD4+ T cell percentage recovery (>35%) rate among the children who started ART aged 1–4 years old with CD4+ T cell <25%. C. Absolute CD4+ T cell count recovery (>750/ul) among children initiating ART aged ≥5 years old with absolute CD4+ T cell counts <350/ul.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494714&req=5

pone.0131591.g004: Sex differences in immune reconstitution amongst the patients started treatment under the pre-2013 WHO guidelines.Sex differences by log rank test are shown as follows: A. Survival after ART initiation. B. CD4+ T cell percentage recovery (>35%) rate among the children who started ART aged 1–4 years old with CD4+ T cell <25%. C. Absolute CD4+ T cell count recovery (>750/ul) among children initiating ART aged ≥5 years old with absolute CD4+ T cell counts <350/ul.
Mentions: We first analyzed treatment outcomes among the 1,244 children in whom ART was initiated based on WHO age criteria (<1yr) or CD4 criteria (described in the Methods). There was no sex difference in survival among these children (p = 0.42, Fig 4A), nor in the time to achieve viral suppression (<50 copies/ml, p = 0.26, not shown). However, even after adjustment for pre-ART CD4 counts or CD4% (see below), CD4+ T cell reconstitution to normal levels for age-matched uninfected children (defined as: CD4% ≥35% in children aged 1–4yr, or CD4 counts >750/ul in children aged ≥5yrs [13]) was more rapid and more complete in females (Fig 4B and 4C). Prior to ART initiation, the differences in CD4% and in CD4 counts did not reach statistical significance comparing male with female children (S2 Table), and, using the Cox hazard model, sex remained a significant covariate in CD4 reconstitution in favor of females in the 1–4yr group (adjusted hazard ratio 1.4, p = 0.030) and also in the ≥5yo group (adjusted hazard ratio 1.4, p = 0.011) (Table 2). In the two age groups of children studied (1–4yo and ≥5yo) in whom the CD4 ART initiation treatment criteria were, respectively, a CD4% <25%, and an absolute CD4 count of <350 cells/ul, recovery to a CD4% of ≥35% and ≥750 cells/ul, respectively, was independently associated with female sex and with pre-ART CD4% and absolute CD4 count, respectively. Pre-ART viral load in either case was not associated with speed of immune reconstitution.

Bottom Line: In a South African cohort of 2,101 HIV-infected children, we observed that absolute CD4+ count and CD4% were significantly higher in ART-naïve female, compared to age-matched male, HIV-infected children.Absolute CD4 count and CD4% were also significantly higher in HIV-uninfected female versus male neonates.The main sex difference in morbidity observed in children initiating ART above CD4 thresholds, above that of TB disease, was as a result of wasting and stunting observed in females with above-threshold CD4 counts (p=0.002).

View Article: PubMed Central - PubMed

Affiliation: Department of Paediatrics, University of Oxford, Oxford, United Kingdom.

ABSTRACT
The incidence and severity of infections in childhood is typically greater in males. The basis for these observed sex differences is not well understood, and potentially may facilitate novel approaches to reducing disease from a range of conditions. We here investigated sex differences in HIV-infected children in relation to antiretroviral therapy (ART) initiation and post-treatment outcome. In a South African cohort of 2,101 HIV-infected children, we observed that absolute CD4+ count and CD4% were significantly higher in ART-naïve female, compared to age-matched male, HIV-infected children. Absolute CD4 count and CD4% were also significantly higher in HIV-uninfected female versus male neonates. We next showed that significantly more male than female children were initiated on ART (47% female); and children not meeting criteria to start ART by >5 yrs were more frequently female (59%; p<0.001). Among ART-treated children, immune reconstitution of CD4 T-cells was more rapid and more complete in female children, even after adjustment for pre-ART absolute CD4 count or CD4% (p=0.011, p=0.030, respectively). However, while ART was initiated as a result of meeting CD4 criteria less often in females (45%), ART initiation as a result of clinical disease in children whose CD4 counts were above treatment thresholds occurred more often in females (57%, p<0.001). The main sex difference in morbidity observed in children initiating ART above CD4 thresholds, above that of TB disease, was as a result of wasting and stunting observed in females with above-threshold CD4 counts (p=0.002). These findings suggest the possibility that optimal treatment of HIV-infected children might incorporate differential CD4 treatment thresholds for ART initiation according to sex.

No MeSH data available.


Related in: MedlinePlus