Abstract
BackgroundCotrimoxazole (CTX) preventive therapy (CPT) reduces opportunistic infections and malaria in HIV-infected patients. In Africa, policies on sustained CPT during antiretroviral therapy (ART) differ between countries. We assessed the safety of discontinuing CPT in stable patients on ART in Uganda.MethodsCOSTOP was a double-blind placebo-controlled trial. Patients aged ≥18 years, on CPT, and stable on ART (CD4 counts ≥250 cells/μL); were randomised to daily oral placebo (PLC group) or cotrimoxazole 960 mg/tablet (CTX group). Co-primary outcomes were: (i) time to first cotrimoxazole-preventable infection, with non- inferiority of PLC defined as the upper one-sided 95% confidence limit of the adjusted hazard ratio(aHR) ≤1.25; and (ii) time to first grade 3/4 haematological adverse event.Findings2180 subjects (1091 PLC; 1089 CTX) were enrolled. 932 PLC and 943 CTX completed the trial after 12 months minimum follow up. Ninety-eight participants (59 PLC; 39 CTX) experienced 120 cotrimoxazole- preventable events, mainly bacterial pneumonia (72 events, 4 deaths PLC); (48 events, 2 deaths CTX). The aHR for time to first event was 1.57 (upper one-sided 95% confidence limit 2.21) in per protocol population (similar results in ITT population). 551 participants (318 CTX; 233 PLC) experienced 1043 haematological adverse events (616 CTX; 427 PLC). Time to the first adverse event, mainly neutropenia, was shorter in the CTX group (aHR 0.70 95%CI 0.59–0.82; log-rank χ2 = 18.08; P<0.0001). 362 (276 PLC, 86 CTX) participants experienced at least one episode of confirmed clinical malaria (P<0.0001).InterpretationIn ART stable patients with CD4 counts ≥250 cells/μL, continued CPT significantly reduces risk of severe bacterial infections and protects against malaria, while discontinuing CPT reduces haematological adverse events.
Highlights
Primary cotrimoxazole preventive treatment (CPT) has been recommended as part of the minimum package of care for people living with HIV/AIDS (PLHIV) in Africa since 2001 [1], a practice supported by clinical trials among antiretroviral naïve patients with advanced HIV disease; which demonstrated that CPT significantly reduces HIV related mortality, bacterial infections, malaria and related hospital admissions.[2,3]
Based on observational studies [12,13,14] and unblinded randomised trials on discontinuing CPT among patients on antiretroviral therapy (ART),[15,16] the World Health Organisation (WHO) in 2014 issued a recommendation that CPT may be discontinued in adults on ART following HIV virologic suppression, but that cotrimoxazole prophylaxis should be continued in settings where bacterial infections and malaria are highly prevalent.[17]
Our study evaluated the benefits and risks of discontinuing CPT in HIV infected adults who are stable on ART in the Uganda
Summary
Primary cotrimoxazole preventive treatment (CPT) has been recommended as part of the minimum package of care for people living with HIV/AIDS (PLHIV) in Africa since 2001 [1], a practice supported by clinical trials among antiretroviral naïve patients with advanced HIV disease; which demonstrated that CPT significantly reduces HIV related mortality, bacterial infections, malaria and related hospital admissions.[2,3]. Subsequent to wide spread availability of antiretroviral therapy (ART), survival and immune function of PLHIV in low and middle income countries have significantly improved, [4] making the added value of sustained CPT alongside ART unclear. This is an important consideration since the CPT intervention represents a substantial increase in overall costs of HIV care programs. We assessed the safety of discontinuing CPT in stable patients on ART in Uganda.
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