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

Lead Research Organisation: MRC/UVRI Uganda Research Unit on AIDS

Abstract

Patients 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.
 
Description Uganda Ministry of Health - HIV Clinical Care Commitee
Geographic Reach Africa 
Policy Influence Type Participation in a national consultation
Impact Development and revision of National antiretroviral therapy guidelines based on data from a research cohort in Uganda
 
Description Collaboration with London School of Hygiene and Tropical Medicine 
Organisation London School of Hygiene and Tropical Medicine (LSHTM)
Department Department of Global Health and Development
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration to conduct an economic evaluation of the interventions tested in the COSTOP trial through a joint study titled "Cost-effectiveness of discontinuing cotrimoxazole preventive therapy in adults". My team and I contribute data gathered from the COSTOP Trial and interpretation of the clinical effect measures and health system cost data to be used in analysis; I have the role of co-investogator, and responsible for regulatory approval and field data collection and contribution to publications of results
Collaborator Contribution The Health Economist at LSHTM lead the study design the study and oversee data collection, modelling analysis and publication of results
Impact Multidisciplinary: clinical, public health and health economics disciplines.
Start Year 2015
 
Description Partnership with The AIDS Support Organisation (TASO) 
Organisation The AIDS Support Organization (TASO)
Country Uganda 
Sector Charity/Non Profit 
PI Contribution MRC funded clinicians supplement patient care of TASO's HIV care clinic in Entebbe.
Collaborator Contribution Source of participants in clinical research. Contribution of ongoing pyschosocial support to people affected by HIV/AIDS who are also MRC research participants. Access to broad community outreach network for dissemination of information on research objectives and research outputs
Impact Overall enhancement of quality of HIV patient care in the Entebbe community as well as developing research capacity
 
Description Partnership with The AIDS Support Organisation (TASO), Entebbe Branch 
Organisation The AIDS Support Organization (TASO)
Country Uganda 
Sector Charity/Non Profit 
PI Contribution Joint provision of HIV clinical care services. Joint development, consultation, training on antiretroviral therapy provision
Collaborator Contribution Source of research participants from the organisations' membership. Contribution of pyschosocial support services to research participants. Contribution of community outreach networks for dissemination of research information and research results
Impact Acceptance and imbedding of MRC research teams and projects in the community. Facilitated communication with community members on MRC clinical research objectives and results
 
Description Dissemination of Trial results in Uganda 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact 1600 hundred stays participants attended 2 half day meetings at which trial results were communicated and discussed including exchange of information on their experiences participating in a blinded RCT and the implications of the study finding for their own ongoing treatment.
the study team held a morning meeting with 6 Heads of Department of Uganda Ministry of Heath and presented the results of the trial. Questions about implications of the result for HIV care policy and costs of HIV care were tabled.
Year(s) Of Engagement Activity 2015
 
Description Uganda National Council of Science and Technology 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Policymakers/politicians
Results and Impact National consultative meeting of research and medicines regulators to discuss ethical appropriateness of further trials on cotrimoxazole prophylaxis among HIV infected patients on antiretroviral therapy. We provided data on effect of Cotrimoxazole on haematologic parameters of untreated HIV infected adults.

A call was made for further studies evaluating continued prophylactic treatment with Cotrimoxazole for HIV infected patients on antiretroviral therapy
Year(s) Of Engagement Activity 2008