Dataset Information

Discontinuing cotrimoxazole preventive therapy in HIV-infected adults who are stable on antiretroviral treatment in Uganda (COSTOP): A randomised placebo controlled trial.

ABSTRACT:

Background

Cotrimoxazole (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.

Methods

COSTOP was a double-blind placebo-controlled trial. Patients aged ?18 years, on CPT, and stable on ART (CD4 counts ?250 cells/?L); 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.

Findings

2180 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 ?2 = 18.08; P<0.0001). 362 (276 PLC, 86 CTX) participants experienced at least one episode of confirmed clinical malaria (P<0.0001).

Interpretation

In ART stable patients with CD4 counts ?250 cells/?L, continued CPT significantly reduces risk of severe bacterial infections and protects against malaria, while discontinuing CPT reduces haematological adverse events.

SUBMITTER: Anywaine Z

PROVIDER: S-EPMC6312229 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

Discontinuing cotrimoxazole preventive therapy in HIV-infected adults who are stable on antiretroviral treatment in Uganda (COSTOP): A randomised placebo controlled trial.

Anywaine Zacchaeus Z Levin Jonathan J Kasirye Ronnie R Lutaakome Joseph Kayiira JK Abaasa Andrew A Nunn Andrew A Grosskurth Heiner H Munderi Paula P

PloS one 20181231 12

<h4>Background</h4>Cotrimoxazole (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.<h4>Methods</h4>COSTOP 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 ( ...[more]

PMID: 30596666

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Project description:BackgroundIntermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended for malaria prevention in HIV-negative pregnant women, but it is contraindicated in HIV-infected women taking daily cotrimoxazole prophylaxis (CTXp) because of potential added risk of adverse effects associated with taking two antifolate drugs simultaneously. We studied the safety and efficacy of mefloquine (MQ) in women receiving CTXp and long-lasting insecticide treated nets (LLITNs).Methods and findingsA total of 1,071 HIV-infected women from Kenya, Mozambique, and Tanzania were randomized to receive either three doses of IPTp-MQ (15 mg/kg) or placebo given at least one month apart; all received CTXp and a LLITN. IPTp-MQ was associated with reduced rates of maternal parasitemia (risk ratio [RR], 0.47 [95% CI 0.27-0.82]; p=0.008), placental malaria (RR, 0.52 [95% CI 0.29-0.90]; p=0.021), and reduced incidence of non-obstetric hospital admissions (RR, 0.59 [95% CI 0.37-0.95]; p=0.031) in the intention to treat (ITT) analysis. There were no differences in the prevalence of adverse pregnancy outcomes between groups. Drug tolerability was poorer in the MQ group compared to the control group (29.6% referred dizziness and 23.9% vomiting after the first IPTp-MQ administration). HIV viral load at delivery was higher in the MQ group compared to the control group (p=0.048) in the ATP analysis. The frequency of perinatal mother to child transmission of HIV was increased in women who received MQ (RR, 1.95 [95% CI 1.14-3.33]; p=0.015). The main limitation of the latter finding relates to the exploratory nature of this part of the analysis.ConclusionsAn effective antimalarial added to CTXp and LLITNs in HIV-infected pregnant women can improve malaria prevention, as well as maternal health through reduction in hospital admissions. However, MQ was not well tolerated, limiting its potential for IPTp and indicating the need to find alternatives with better tolerability to reduce malaria in this particularly vulnerable group. MQ was associated with an increased risk of mother to child transmission of HIV, which warrants a better understanding of the pharmacological interactions between antimalarials and antiretroviral drugs.Trial registrationClinicalTrials.gov NCT 00811421; Pan African Clinical Trials Registry PACTR 2010020001813440 Please see later in the article for the Editors' Summary.

Project description:Cotrimoxazole (CTX) prophylaxis is recommended by the World Health Organization (WHO) for HIV-1-infected individuals in settings with high infectious disease prevalence. The WHO 2006 guidelines were developed prior to the scale-up of antiretroviral therapy (ART). The threshold for CTX discontinuation following ART is undefined in resource-limited settings.Between 1 February 2012 and 30 September 2013, we conducted an unblinded non-inferiority randomized controlled trial of CTX prophylaxis cessation versus continuation among HIV-1-infected adults on ART for ? 18 mo with CD4 count > 350 cells/mm3 in a malaria-endemic region in Kenya. Participants were randomized and followed up at 3-mo intervals for 12 mo. The primary endpoint was a composite of morbidity (malaria, pneumonia, and diarrhea) and mortality. Incidence rate ratios (IRRs) were estimated using Poisson regression. Among 538 ART-treated adults screened, 500 were enrolled and randomized, 250 per arm. Median age was 40 y, 361 (72%) were women, and 442 (88%) reported insecticide-treated bednet use. Combined morbidity/mortality was significantly higher in the CTX discontinuation arm (IRR = 2.27, 95% CI 1.52-3.38; p < 0.001), driven by malaria morbidity. There were 34 cases of malaria, with 33 in the CTX discontinuation arm (IRR = 33.02, 95% CI 4.52-241.02; p = 0.001). Diarrhea and pneumonia rates did not differ significantly between arms (IRR = 1.36, 95% CI 0.82-2.27, and IRR = 1.43, 95% CI 0.54-3.75, respectively). Study limitations include a lack of placebo and a lower incidence of morbidity events than expected.CTX discontinuation among ART-treated, immune-reconstituted adults in a malaria-endemic region resulted in increased incidence of malaria but not pneumonia or diarrhea. Malaria endemicity may be the most relevant factor to consider in the decision to stop CTX after ART-induced immune reconstitution in regions with high infectious disease prevalence. These data support the 2014 WHO CTX guidelines.ClinicalTrials.gov NCT01425073.

Dataset Information

Discontinuing cotrimoxazole preventive therapy in HIV-infected adults who are stable on antiretroviral treatment in Uganda (COSTOP): A randomised placebo controlled trial.

Background

Methods

Findings

Interpretation

Publications

Discontinuing cotrimoxazole preventive therapy in HIV-infected adults who are stable on antiretroviral treatment in Uganda (COSTOP): A randomised placebo controlled trial.

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