Trials show further benefits for cotrimoxazole in children and adults
Nathan Geffen, CSSR
Cotrimoxazole is more than forty years old and costs a few dollars per patient per month. Amazingly, new benefits continue to be found for this broad-spectrum antibiotic. Results from three randomised clinical trials of cotrimoxazole, one for adults and two for children, have recently been presented.
Cotrimoxazole prevents malaria in adults on ART with high CD4 counts
At CROI 2014, Christina Polyak of the Military HIV Research Unit at Walter Reed presented the results of a randomised non-inferiority trial of cotrimoxazole prophylaxis (CTX) conducted in Homa Bay District Hospital in Western Kenya.  This is a malaria endemic area.
The World Health Organisation (WHO) recommends CTX for all adults with HIV with CD4 counts < 350 cells/mm3. In settings with high HIV prevalence and limited resources, the WHO recommends CTX for all adults with HIV. The Kenyan guidelines follow this recommendation. However these guidelines were developed prior to the scale-up of ART. The threshold for discontinuing CTX is undefined after patients start ART.
Discontinuing CTX means a reduced pill burden for patients, potentially less drug toxicity and less resistance, as well as lower costs. The aim of this study was to find out if continuing CTX reduces morbidity in people on ART whose immune systems have recovered. An earlier trial in Uganda found reduced diarrhea and malaria in patients on ART with CD4 counts higher than 200 cells/mm3.  An ongoing study in Uganda called COSTOP is also looking at this question. 
The study described by Polyak was a non-blinded, non-inferiority randomised trial, open to HIV-positive participants on ART over 18 with CD4 counts of 350 cells/mm3 or more. Pregnant women and people on second-line ART were excluded. Participants were provided bed nets and water filters. The primary endpoint was a composite measure of morbidity (malaria, pneumonia and diarrhaea) and non-trauma mortality. Severe adverse events were a secondary endpoint.
The study took place from February 2012 to September 2013. Patients were followed up for a year.
Of 538 people assessed, 500 were randomised, with exactly 250 allocated to CTX and 250 allocated to stop CTX. 245 patients in each arm completed follow-up.
There were no significant differences between the arms at baseline. About 70% were female, average age was 40, median CD4 count was just under 600 cells/mm3, median time on ART was 4.5 years and nearly 90% of participants reported using bed nets.
The CTX arm did significantly better on the primary endpoint (34 cases at an incidence of 13.4 / 100 person years vs 77 cases at an incidence of 30.4 per 100 person years; incidence rate ratio [IRR]: 2.27, 95%CI: 1.52-3.38; p < 0.001).
This was driven solely by malaria (1 case vs 33; IRR: 33.02, 95%CI: 4.52-241.02; p < 0.001). Only one malaria case – in the stop CTX arm – was serious and required hospitalisation. There were no significant differences in mortality, diarrhea or pneumonia. For diarrhea, there were 25 cases in the CTX arm versus 34 in the discontinuation one, but the IRR does not show a trend (p=0.24).
There was no significant difference in serious adverse events. There were actually fewer on the CTX arm (9 vs 19; IRR: 2.0, 95%CI: 0.9-4.44; p=0.088).
Polyak pointed out that the study had limitations. It was unblinded which might have affected clinician care decisions and patients off CTX might have sought care more often. Also the study was confined to an endemic malaria area, had very high retention and was short.
Cotrimoxazole trials in children on ART
The WHO recommends CTX for children without HIV born to mothers with HIV, from six weeks until the end of breastfeeding.
In January, the ARROW trial team published the results of an open-label randomised non-inferiority trial in the NEJM.  This trial showed the benefit of children with HIV continuing to take CTX. Children in Uganda and Zimbabwe older than three were included if they had been on ART for more than 96 weeks, were using insecticide treated bed nets in malaria areas and had not had Pneumocystis jirovecii pneumonia. 382 and 376 children were randomised to stop or continue CTX respectively.
At baseline, the children had been on ART for a median of just over two years (IQR: 1.8 to 2.3). median age was nearly eight years (IQR: 4.6 to 11.1), and median CD4 percentage was 33% (IQR: 26 to 39). Median follow-up was just over two years (IQR: 1.8 to 2.2).
Children who stopped CTX had higher rates of hospitalisation or death than those who continued (72 [19%] vs. 48 [13%]; HR: 1.64; 95%CI: 1.14-2.37; p=0.007). But deaths were not significantly different: two in the stopped CTX arm vs three in the CTX arm. The malaria hospitalisations in the stopped CTX arm were 49, while there were 21 in the CTX arm. There were 53 hospitalisations for other infections in the stopped CTX arm and 25 in the CTX arm.
There were significantly more grade 4 adverse events in the CTX stop group (HR: 2.04; 95% CI 0.99-4.22; p=0.05). Most of these were due to anemia (12 vs 2).
A poster at CROI also showed that children on CTX in ARROW had lower inflammatory biomarkers than those in the stopped CTX arm. 
Young Ugandan children trial
At CROI a late-breaker poster by Jaco Homsy and colleagues showed the results of a CTX trial in Uganda.  The children in this trial were younger than in ARROW and HIV uninfected for the most part. The trial design is complex.
The trial enrolled 203 HIV-exposed infants who were between six weeks and nine months old. They were prescribed daily CTX until breastfeeding ended and their HIV status was confirmed. After breastfeeding, 185 children remained in follow-up and without HIV. They were randomised to continue or stop CTX until two years old. At two, the 91 children who continued CTX were randomised again to continue or discontinue CTX until they were four years old.
Also followed up for comparison were 48 children with HIV on continuous CTX prophylaxis and 100 children unexposed to HIV who never received CTX prophylaxis.
Of the 185 HIV-exposed children 152 (82%) and 146 (79%)were followed to ages four and five respectively.
CTX to age four resulted in a 43% reduction in malaria(IRR: 0.57; 95%CI, 0.49-0.66; p<0.001). Throughout the trial, malaria incidence was lowest among children who received CTX and highest among HIV-negative unexposed children who did not receive CTX prophylaxis. There were no significant differences in serious adverse events, hospitalisations, or deaths among HIV-exposed, HIV-unexposed, and HIV-infected children. There was no evidence of malaria incidence rebound in the year following stopping CTX at age two or four, but incidence increased significantly from age four to age five among children who stopped CTX at age four.
In the 203 HIV-exposed children on CTX there were 142 malaria episodes and a malaria incidence of 1.35 episodes per person year.
In the 48 children children on CTX who were infected with HIV there were also 142 malaria episodes and a malaria incidence of 1.93 per person year.
In the 100 HIV unexposed children not on CTX there were 674 malaria episodes and a malaria incidence of 4.63 per person year.
HIV-exposed children who continued CTX to age four had a 47% lower risk of malaria compared to children who stopped CTX at age two or after the end of breastfeeding.
These trials show that CTX reduces malaria in both adults and children with HIV. CTX also reduces malaria in children exposed to HIV until at least the age of four, probably beyond. It also reduces other infections that require hospitalisation in children with HIV.
New WHO guidelines will likely consider the results of these trials and recommend continued CTX for adults and children with HIV or exposed to HIV in malaria endemic areas. Children with HIV in non-malarial areas might also benefit from CTX.
These trials suggest CTX might be an effective malaria prophylactic irrespective of HIV status. One question put to Christina Polyak at CROI was whether there could be a perception of AIDS exceptionalism. The implication was why offer CTX to people with HIV stable on ART for the prevention of malaria and not people without HIV? Also what are the public health consequences of mass prophylaxis against malaria using cotrimoxazole and the possible development of population resistance over time, perhaps not only for malaria? These are complex questions that researchers and patients have to grapple with.
1. Polyak CS et al. 2014. CTX Prophylaxis discontinuation among ART-treated adults: a randomised non-Inferiority trial. 21st Conference on Retroviruses and Opportunistic Infections, Boston, 3-6 March. Oral abstract 98.
2. Campbell JD et al. HIV-infected Ugandan adults taking antiretroviral therapy with CD4 counts <200 cells/IL who discontinue cotrimoxazole prophylaxis have increased risk of malaria and diarrhea. Clin Infect Dis. 2012 Apr;54(8):1204-11. doi: 10.1093/cid/cis013.
3. Munderi P. 2010. Safety of discontinuing co-trimoxazole prophylaxis among Ugandan adults on antiretroviral therapy (ART). (COSTOP)
4. Bwakura-Dangarembizi M et al. A Randomized Trial of Prolonged Co-trimoxazole in HIV-Infected Children in Africa. N Engl J Med 2014; 370:41-53.
5. Prendergast AJ et al. Lower inflammatory biomarkers in children randomised to prolonged cotrimoxazole prophylaxis. 21st Conference on Retroviruses and Opportunistic Infections, Boston, 3-6 March. Poster abstract 914.
6. Homsy J et al. Four year cotrimoxazole prophylaxis prevents malaria in HIV-exposed children: a randomised trial. 21st Conference on Retroviruses and Opportunistic Infections, Boston, 3-6 March. Poster abstract 860LB.