on ART for more than two years who continued taking daily cotrimoxazole had
significantly fewer hospitalisations for malaria as well as for non-malarial
infections (notably pneumonia, sepsis and meningitis), compared to children who
stopped this treatment, researchers from Uganda and Zimbabwe reported at the 20th Conference on Retroviruses and
Opportunistic Infections (CROI 2013) in
Atlanta this week.
of continued use of cotrimoxazole persisted across all age groups and CD4
advocate the continued use of cotrimoxazole long term in children and
adolescents on ART in resource-poor countries, and recommend that current guidelines
be revised accordingly. However, they caution, for this to happen health care
systems and supply-chain logistics must be strengthened to avoid stock-outs.
a sub-study of the ARROW trial reported earlier this week, which showed that
children did as well on antiretroviral therapy without routine laboratory
monitoring of CD4 cell counts or drug side-effects as those who received regular
monitoring over four years of follow-up. The
trial recruited over 1200 symptomatic HIV-infected infants and children in
Uganda and Zimbabwe.
is a cheap, widely available antibiotic, easy to use with no adverse side-effects. It is commonly used in low- and middle-income countries for a wide
range of fungal and bacterial infections. Cotrimoxazole
prophylaxis is known to reduce death and disease – including malaria, pneumonia and
diarrhoea – in HIV-positive adults and children before they start ART.
adult DART study showed the benefits of continuation of cotrimoxazole for the
first 18 months on ART. Other adult studies are ongoing.
the long-term effect of cotrimoxazole in children on ART is unknown; there are
no trials on discontinuation of cotrimoxazole in children and no data from
current World Health
Organization (WHO) guidelines on cotrimoxazole prophylaxis recommend cotrimoxazole continuation, they also state that:
“Children over 5 years of age with good adherence after more than six months on
ART, full clinical recovery and CD4 counts over 350 cells/mm3, may discontinue cotrimoxazole.”
researchers chose to look at whether stopping daily cotrimoxazole in children
over three years of age, and on ART for at least 96 weeks, had a similar outcome
determined by hospitalisation or death as those continuing daily cotrimoxazole. Co-primary
endpoints were hospitalisation or death (efficacy) and any grade 3 or 4 adverse
events (AEs; safety).
A total of 758 children
from the ARROW trial with a median of 2.1 years on ART (interquartile range IQR1.8-2.2)
were randomised to stop (382) or continue (376) daily cotrimoxazole. Eligibility
included being over three years of age, on ART for more than 96 weeks,
currently on daily cotrimoxazole, using an insecticide-treated bed net if
living within a malaria-endemic area and having no previous pneumocystis
jirovecii pneumonia (PCP) episodes.
over 1000 children were eligible and approached for consent. However, caregivers of 25% of
these children declined because they had faith in cotrimoxazole, having used
it for their children before ART became available.
randomisation, the median age was seven (IQR: 4-11) years and the CD4 percentage
was 33 (IQR: 26-29). The two groups were
similar in age, sex, CD4 percentage and cell count, and years on ART.
improvement in immune status was
substantial when compared to the time of enrolment in the trial. Median
follow-up was 2.1 years; nine children withdrew or were lost. Adherence to the
strategy was very high in both groups.
children who stopped cotrimoxazole there was a 60% increase in hospitalisation
or death, hazard ratio HR: 1.57, 95%CI: 1.09-2.26, p=0.007. Age,
sex, clinically indicated compared to routine CD4 test monitoring, and facility attended made no
difference to the outcomes.
there was some variation in cotrimoxazole effect by CD4 count, the benefits of
continuing cotrimoxazole were greatest in those with CD4 percentage was equal to or
above 30%, HR: 2.15, 95% CI: 1.30-3.54; 19% who stopped compared to 10% who
continued were hospitalised.
were few deaths, with no real difference between the two groups: 2/382 (0.5%)amongst those those who stopped and 3/376 (0.8%) of those who continued, respectively.
primary endpoint was driven by hospitalisation. Among those who stopped cotrimoxazole,
the increased number of hospitalisations for both malaria (49 compared to 20)
and non-malarial infections (53 compared to 25; notably pneumonia, sepsis and
meningitis) was quite considerable.
children who stopped cotrimoxazole, there was a two-fold increased risk for
getting malaria, HR: 2.10, 95% CI: 1.43-3.09, p<0.0001. In addition, the
parasite density was also higher among those who stopped cotrimoxazole and went on to develop
risks for grade 3 and 4 AEs were similar (HR: 1.17, 95% CI: 0.82-1.68,
among those stopping C cotrimoxazole the risks for grade 4 AEs were
significantly higher (HR: 2.03, 95% CI: 0.98-4.18, p=0.05). This was mostly
because of anaemia, with 12 cases in those who stopped compared to just two in
those who continued. Overall, the levels
of haemoglobin were lower among those who stopped.
there were no substantive differences over time in changes in CD4 count, weight
and height, there was a tendency to a higher weight in those who continued.
researchers concluded, from this first randomised clinical trial in children with a background of bacterial and protozoan infections, that continuing cotrimoxazole
after more than two years on ART is beneficial for HIV-infected children in
the presentation, a participant in the audience representing WHO confirmed that the cotrimoxazole
prophylaxis guidelines would be revised this year.