CROI 2015: Stopping Co-trimoxazole During ART Raises Risk of Bacterial Illness and Malaria

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Stopping trimethoprim/sulfamethoxazole (Co-trimoxazole) prophylaxis increases the risk of serious bacterial infections and malaria, even at high CD4 cell counts, among people with HIV taking antiretroviral therapy (ART) in Uganda, according to results of a randomized trial presented by Jonathan Levin of the UK Medical Research Council at the recent 2015 Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.

[Produced in collaboration with Aidsmap]

Co-trimoxazole (TMP-SMX; brands include Bactrim and Septra, generics also available) is a sulfa-based combination antibiotic that is used to treat bacterial infections. Taken regularly as prophylaxis, it provides protection against a variety of bacterial infections and also against malaria (caused by a protozoan).

Co-trimoxazole prophylaxis is recommended for all adults with HIV who have CD4 T-cell counts below 350 cells/mm3 and for all people with symptomatic HIV disease (WHO stages 3 or 4) regardless of CD4 cell count.

Updated WHO guidelines issued in December 2014 recommended that co-trimoxazole prophylaxis could be stopped in adults taking antiretroviral therapy if they are virally suppressed and show evidence of immune recovery. However, the guidance noted that the quality of the evidence to support this conditional recommendation was low. In settings where bacterial infections and malaria are prevalent, co-trimoxazole prophylaxis can be continued regardless of CD4 cell count, the guidelines state.

Long-term co-trimoxazole treatment increases the pill burden for people taking ART, which may compromise adherence, and may also cause toxicity such as neutropenia (low levels of white blood cells called neutrophils which fight off bacterial and fungal infections). It is also an additional burden for pharmacies to manage co-trimoxazole stocks, and the additional disease prevention benefit for people on stable ART in settings with a high burden of bacterial infections is unclear.

In order to answer these questions, the Medical Research Council designed a study to test whether it is safe to stop co-trimoxazole prophylaxis in a setting with a high frequency of infections that are preventable by co-trimoxazole.

The COSTOP study randomized adults on ART with CD4 cell counts above 250 cells/mm3 to continue co-trimoxazole prophylaxis or receive a placebo. The study enrolled 2180 participants at 2 sites in rural Uganda. Participants had a median CD4 count of 518 cells/mm3 and had completed a median of 4 years of antiretroviral treatment. 93% of participants were followed for at least 1 year.

The study was blinded to investigators and participants. The primary endpoints were the time to death or the first clinical event that was preventable by co-trimoxazole, along with grade 3 and 4 hematological adverse events. The study assessed efficacy by intent-to-treat analysis and by a per-protocol analysis in which participants were evaluable if they had taken at least 80% of their pills for each period between study visits.

After 2 years of follow up, the per-protocol analysis showed significantly more primary endpoints in the placebo arm compared with the co-trimoxazole arm (2.94 vs 1.84 per 100 person-years; adjusted HR 1.57, 90% CI 1.12-2.21).

The most frequently occurring events were bacterial pneumonia (33 in the placebo arm vs 20 in the co-trimoxazole arm) and recurrent upper respiratory infections (4 vs 5, respectively). There were 6 deaths considered to be preventable by cotrimoxazole, 4 in the placebo arm and 2 in the co-trimoxazole arm (1 of these was due to malaria).

Hematological adverse events were significantly less frequent in the placebo arm than in the co-trimoxazole arm (10.6 vs 15.3 per 100 person-years; adjusted HR 0.70, 90% CI 0.59-0.82). Severe (grade 4) neutropenia occurred in a substantial minority of participants in both arms of the study, but it was more frequent in the co-trimoxazole arm (8.2% vs 5.0%).

Malaria was significantly less frequent among those who received co-trimoxazole (4.1 vs 13.9 cases per 100 person-years; adjusted HR 3.43, 95% CI 2.69-4.38). Hospitalization was also more frequent in the placebo group, especially for malaria.

Co-trimoxazole recipients had significantly lower CD4 cell counts (469 vs 495 cells/mm3) and were more likely to experience no increase in CD4 cells during the first 48 weeks of the study.

The researchers concluded that this study did not demonstrate that stopping co-trimoxazole was non-inferior to continuing prophylaxis.

3/20/15

Reference

P Munderi, JB Levin, Z Anywaine, et al. Is It Safe to Stop Cotrimoxazole in Adults on ART: COSTOP, a Noninferiority RCT. 2015 Conference on Retroviruses and Opportunistic Infections. Seattle, February 23-24, 2015. Abstract 94.