Background: In Uganda, cotrimoxazole (CTX) prophylaxis is recommended as part of a package of comprehensive care. The benefits of continuing CTX in African patients who have regained immune competence through ART are not known particularly in the light of potential disadvantages such as co-toxicity with ART and increased pill burden leading to possible diminished adherence to HIV treatment The objective of COSTOP was to assess the risks and benefits of discontinuing CTX in patients achieving sustained immune restoration.
Methods: From January 2011 HIV-infected patients aged >18 years, stable on ART with confirmed CD4 restoration to 250 cells/mm3 and above who consented to join the double-blind trial were randomised 1:1 to one oral tablet of 960 mg of CTX daily or matching placebo. Co-primary outcome measures were (1) time to first CTX-preventable event excluding malaria, (2) time to the occurrence of the first grade 3 or 4 haematological adverse event (AE). Patients attended study clinics monthly during the first 3 months post-randomisation and 3-monthly thereafter for a range of 1 – 3 years. An endpoint review committee adjudicated the efficacy endpoints.
The analysis of the efficacy assesses the non-inferiority of the outcome in the placebo arm compared to the control; non-inferiority required the upper limit of the 90% confidence interval to be less than a 25% increased risk of an endpoint event on the placebo arm. The primary safety analysis assesses the reduction in haematological adverse events in the placebo arm. The study had a minimum of 80% power based on assumptions concerning endpoints in the CTX arm.
Results: 2180 patients were enrolled from two sites in SW Uganda; 74% female, median age 41, CD4 count 518, months on ART 48. 93.3% patients completed at least a year in the study. In the per protocol analysis a total of 124 (54 CTX, 70 placebo) first CTX preventable adjudicated events occurred, hazard ratio adjusted for site and CD4 stratum (aHR) 1.35 (90% CI 1.00,1.81), a difference of 0.9/100 person years. These findings were confirmed in ITT and sensitivity analyses. The incidence of first grade 3 or 4 haematological adverse events was reduced in the placebo arm, aHR 0.70, 95% CI 0.59, 0.82.
Conclusions: Although there was a significant reduction in grade 3 or 4 haematological adverse events in patients allocated to stopping CTX non-inferiority of this strategy with respect to CTX preventable events was not demonstrated.