Safety of discontinuing Cotrimoxazole Prophylaxis among African adults on ART. A randomised controlled trial

Lead Research Organisation: University College London

Abstract

atients with HIV infection often have severe damage to the body?s immune system and are at risk of various other infections (so called opportunistic infections) that may cause disease and death. Daily intake of the antinfective medication: cotrimoxazole (CTX) has been shown to be highly effective in reducing the frequency of these infectious complications of HIV disease. This prophylactic treatment with cotrimoxazole has therefore become standard practice for HIV infected patients. In industrialised countries, after the introduction of antiretroviral (ARV) treatments for HIV infection, studies showed that the additional prophylaxis with cotrimoxazole could safely be discontinued once patients showed evidence of restoration of their immune function. For some years now, many HIV infected patients in Africa have also started to receive antiretroviral treatments. ARVs help to restore a person?s immune system (although they cannot cure a person from HIV infection) and the provision of ARVs has changed the health of thousands of HIV infected people and dramatically reduced the death rate among those who take them. It may also be possible to discontinue CTX prophylaxis among patients whose immune system is working well again, but no studies have demonstrated the safety of this practice in Africa. Since ARV treatment is lifelong, it would be desirable; in order to reduce pill burden, reduce the risk of possible treatment side effects and contribute to better ARV treatment adherence and reduction of treatment costs. The planned study in Uganda will address this important question among African patients by investigating whether patients who are responding well to ARV treatment can discontinue prophylactic treatment with CTX without a substantially higher risk of becoming ill.

Technical Summary

Cotrimoxazole (CTX) is a broad spectrum antimicrobial medication that is widely used as primary and secondary prophylaxis against opportunistic infections among HIV infected individuals. On the other hand, treatment of HIV infection with antiretroviral drugs permits restoration of the immune system with a resultant reduction in susceptibility to many of the opportunistic infections to which people with HIV are prone. Research done in industrialised countries has shown that it is not necessary to continue prophylactic treatment with CTX prophylaxis in patients on antiretroviral therapy (ART); and it is standard practice in industrialised countries to discontinue prophylactic treatment with CTX once immune restoration to a CD4 count of 200 cells/mm3 has been documented. In Africa, where there is a different spectrum of opportunistic infections among HIV infected patients, but where there is also increasing access to ART for HIV infected patients, there have been no controlled studies done on whether or not this additional prophylactic treatment with CTX can safely be discontinued once patients are stable on ART. Clinicians in Africa are uncertain about the safety of discontinuing CTX, yet continued indefinite administration of CTX for has the potential disadvantages of a high pill burden, possibility of side effects and increased costs. It is therefore important to establish in a controlled trial, whether CTX prophylaxis can be safely discontinued once patients on ART have regained their immune competence. The proposed non-inferiority trial will investigate the safety of stopping CTX medication among HIV infected patients who are also on ART, once they have achieved a CD4 count level of 250 cells/mm3 and above. HIV infected adults receiving both ART and CTX will be randomised to either continue with their combined medication (control group), or to receive their current ART plus CTX placebo (experimental group). About 2000 patients will be recruited in total at two study clinics of the MRC Uganda Research Unit on AIDS. They will be followed 3-monthly intervals for a median of 2 years and whenever ill. The primary outcome measure will be the incidence of serious CTX preventable clinical events and side effects of CTX. Secondary outcome measures will include the incidence of all clinical events including malaria episodes, mean change in CD4 count and other haematological parameters after 12 months on the trial, time to failure of ART, serious adverse events and compliance with ART regimens, trial drug regimens and use of insecticide- treated mosquito nets.

Publications

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Guideline Title Consolidated Guidelines for the Prevention and Treatment of HIV and AIDS in Uganda. 2nd edition September 2018
Description Revised Cotrimoxazole prophylaxis policy Uganda
Geographic Reach National 
Policy Influence Type Citation in clinical guidelines
Impact Routine cotrimoxazole prophylactic therapy (CPT) has been recommended since about the year 2000 to be provided to all HIV infected patients in Africa and beyond. Our research has shown that it can be safe to stop CPT once HIV infected patients have regained their immune competence due to antiretroviral therapy. In such patients, the discontinuation of CPT is associated with a decreased risk of haematological side effects due to cotrimoxazole and reduced pill burden. At the health systems level, discontinuation of CPT leads to reduced costs. The revised HIV care guidelines imply that CPT should not generally be provided to HIV infected patients, but only to certain specified high risk groups such as people whose infection is not virally supressed or to pregnant women etc. We expect that other resource restricted countries will also introduce similar policy changes.
 
Description Training budget of the MRC Uganda Research Unit on AIDS - for PhD research of Dr Ronnie Kasirye
Amount £36,000 (GBP)
Organisation MRC/UVRI Uganda Research Unit on AIDS 
Sector Public
Country Uganda
Start 01/2013 
End 06/2016
 
Description MITU 
Organisation National Institute for Medical Research, Tanzania
Department Mwanza Intervention Trials Unit (MITU)
Country Tanzania, United Republic of 
Sector Public 
PI Contribution Collaboration on study steering committee; support of research design and planning; scientific advice during study implementation and preparation of publications; contribution to senior management team of the Unit.
Collaborator Contribution Collaboration on study steering committee; coordination of research with MoH Tanzania; planning and implementation of four cross-sectional studies in phase 1 of the award. Preparation of publications.
Impact Completion of a population based survey on NCDs and HIV infection, a health facility (HF) survey, qualitative studies at population and HF level; costing data collection - all within phase 1 of the work under this award. Four publications in preparation.
Start Year 2011
 
Description MRC Uganda 
Organisation MRC/UVRI Uganda Research Unit on AIDS
Country Uganda 
Sector Public 
PI Contribution Collaboration on study steering committee; support of research design and planning; scientific advice during study implementation and preparation of publications; contribution to senior management team of the Unit.
Collaborator Contribution Collaboration on study steering committee; coordination of research with MoH Uganda; planning and implementation of cross-sectional studies in phase 1 of the award. Preparation of publications.
Impact Outputs: Completion of a population based survey on NCDs and HIV infection, a health facility (HF) survey, qualitative studies at population and HF level; costing data collection - all within phase 1 of the work under this award. Four publications in preparation.
Start Year 2011
 
Description MRC Uganda 
Organisation MRC/UVRI Uganda Research Unit on AIDS
Country Uganda 
Sector Public 
PI Contribution Collaboration on study steering committee; support of research design and planning; scientific advice during study implementation and preparation of publications; contribution to senior management team of the Unit.
Collaborator Contribution Collaboration on study steering committee; coordination of research with MoH Uganda; planning and implementation of cross-sectional studies in phase 1 of the award. Preparation of publications.
Impact Outputs: Completion of a population based survey on NCDs and HIV infection, a health facility (HF) survey, qualitative studies at population and HF level; costing data collection - all within phase 1 of the work under this award. Four publications in preparation.
Start Year 2011
 
Description MoH Uganda 
Organisation Ministry of Health, Uganda
Department Non Communicable Diseases
Country Uganda 
Sector Public 
PI Contribution Collaboration on study steering committee; provision of new data on NCDs and on the health services for NCDs in SW Uganda.
Collaborator Contribution Collaboration on study steering committee; approval of research plans; support to study implementation; recognition of research results on current health services; suggestions for intervention design for activities to be conducted in phase 2 of the award.
Impact Outputs: Completion of a health facility (HF) survey. Publications in preparation.
Start Year 2011
 
Description Dissemination meeting with senior colleagues from Moh, International Diabetes Foundation NCD advisers 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Policymakers/politicians
Results and Impact Final dissemination workshop at end of trial
Year(s) Of Engagement Activity 2017
 
Description Feedback MoH 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Presentation of research results from phase 1 and 2 of the award to policy makers and district health services managers in Uganda and Tanzania. Discussion of potential policy implications, and of activities for final phases of the award.

Repeated contact with MoH officials and District Medical Officers in Uganda and Tanzania

National NCD programme leaders and district health services managers in Uganda and Tanzania confirmed earlier committments made to collaborate closely on activities of the award. Subsequently we observed a tangible increase in the support of efforts with respect to the control of non-communicable diseases in their areas of jurisdiction.
Year(s) Of Engagement Activity 2013,2014,2015
 
Description Presentation to MoH Uganda 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Presentation of trial results to policy makers and technical experts of the Ministry of Health in Uganda
Year(s) Of Engagement Activity 2013