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Cotrimoxazole prophylaxis provides no benefit for HIV-exposed uninfected children
Carole Leach-Lemens, 2016-02-25 01:10:00
current guidelines, prolonged use of cotrimoxazole (CTX) may not be necessary
for HIV-exposed uninfected (HEU) children in low mortality, non-malarial
settings with low risk for late mother-to-child transmission through
breastfeeding, Roger L. Shapiro told participants on Tuesday at the Conference on
Retroviruses and Opportunistic Infections (CROI 2016) in Boston.
cotrimoxazole did not improve 18-month survival or clinical outcomes in this first
randomised controlled trial of 2848 HIV-exposed uninfected children in southern
Botswana, a non-malarial region. The number of deaths was similar in the CTX
and placebo arms, 30 and 34 respectively. Hospitalisations, grade 3/4
diagnoses, and grade 3/4 anaemia did not differ between the CTX and placebo arms,
(10.8% vs. 12.4%, p = 0.24, 16.1% vs. 17.8%, p = 0.36 and 8.0% vs. 8.2%, p = 0.84,
in the CTX arm experienced grade 3/4 neutropenia compared to the placebo arm,
7.9% and 5.8%, p = 0.05, respectively. However, this had no clinical
is a feasible, well-tolerated and inexpensive drug, widely available in
resource-poor settings. It is effective in reducing HIV-related mortality and
morbidity, notably in areas where malaria and/or severe bacterial infections
prophylaxis is recommended for infants, children and adolescents with HIV,
regardless of clinical and immune conditions. It is also recommended for
HIV-exposed infants four to six weeks of age and continued until HIV infection
has been excluded by an age-appropriate test to determine a final diagnosis
when breastfeeding ends.
with high coverage of prevention of mother-to-child transmission (PMTCT) interventions and early infant diagnosis the added
benefits of CTX prophylaxis for HIV-exposed uninfected infants who are
breastfed has been questioned.
shown that CTX reduces morbidity and mortality among HIV-infected children in
Zambia, Cote d’Ivoire, Malawi, Tanzania and Uganda. A 52% reduction in
mortality among HIV-exposed uninfected infants taking CTX was observed in
Malawi. However, no randomised trials or studies in non-malarial areas have evaluated
its efficacy among HIV-exposed uninfected infants.
uninfected children do experience a higher mortality rate compared to children
who have not been exposed to HIV. The increased rates of mortality can be as
much as four to five-fold higher. The mechanism of this vulnerability is poorly
Study recruited HIV infected mothers and their HEU children at three sites (a
city, a town and a village) in southern Botswana. Mothers were enrolled from 26
weeks gestation to 34 days after giving birth. Of the total 3334 women close to
80% were enrolled in a maternity ward.
uninfected children were randomised to receive either double-blinded CTX (1423)
or placebo (1425) from 14 to 34 days of life until 15 months of age, death or
closure. The children were seen every one to three months until 18 months of age.
Those diagnosed with HIV after randomisation moved to open-label CTX. Mothers
chose their preferred feeding method: either formula provided by the Botswana
government or breastfeeding supported by maternal or infant antiretroviral
prophylaxis. Breastfed infants were randomised to either six or 12 months
objective was child survival between randomisation and 18 months by randomised
treatment arm (cotrimoxazole and placebo). A secondary breastfeeding objective
was HIV-free survival at 18 months by randomised feeding arm.
The study ran
from May 2011 until April 2015 when at the recommendation of the Data and
Safety Monitoring Board it was stopped since it was unlikely to show any
benefit from CTX.
follow-up was minimal with 95% of infants completing the study follow-up. Close to three quarters received continuous
study drug until 15 months of age, death or study closure in both the CTX and
placebo arms, 73% and 72%, respectively
characteristics of mother and infants were almost identical in both arms. Maternal
median age was 31 and 30 years, maternal median CD4 cell count: 504 and 508,
median birth weight: 2.97 and 2.90 kg in the CTX and placebo arms, respectively.
In both arms only 21% breastfed and most infants were randomised between 28 and
34 days old.
There was no
significant difference in the cumulative proportion dying between randomisation
and 18 months.
death at 18 months of age was 2.4% compared to 2.6% (difference: 0.2%; 95% CI:
1.0%-1.5%), for CTX and placebo, respectively.
There were no
significant differences in causes of death by study arm. Diarrhoeal disease accounted for 53% (34) and
pneumonia 23% (15).
isolates were grown from 446 routine stool specimens collected at randomisation
or at three and six months. While there were no differences at randomisation
there was significantly more resistance to e-coli at three and six months in
the CTX arm. (for further analysis of this finding see: K.Powis poster 784).
Overall 20% (569)
of infants were breastfed; fewer than anticipated limiting the power of this
secondary analysis. Early weaning was common. There were few deaths (11 or
2.3%) by 18 months of age among those who breastfed. Of the 11 deaths, eight
occurred among those randomised to breastfeed for six compared to three among
those breastfeeding for 12 months. After six months there were only three
deaths in the six-month group compared to two in those breastfeeding for 12.
CTX was well
tolerated even at two weeks of life, a novel finding.