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

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.

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.