HIV Care Research Programme / Primary Prevention of Invasive Cryptococcal Disease (CRYPTOPRO Trial)

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

Abstract

Cryptococcal disease (a fungus infection) has been documented as a frequent infection among patients with advanced HIV progression in Africa. The disease can in principle be treated with fluconazole, but treatment is often unsuccessful and cryptococcal disease often ends fatal. It would therefore be helpful if a cost-effective prophylactic intervention strategy could be found. This would help both those patients who cannot access ART, and those who wait to start ART or just have started it (but have not yet regained their immuno-competence). It has been postulated that regular fluconazole medication may be a good prophylactic strategy against cryptococcal disease. Our study is a randomised placebo controlled trial to explore the effectiveness of this strategy.

Technical Summary

Purpose: To determine if routine fluconazole prophylaxis in HIV infected Ugandans can reduce morbidity and mortality from invasive cryptococcal disease. Cryptococcal disease has been documented as an important optimistic infection in HIV infected patients in Africa and is associated with high mortality. The research question is relevant both for patients who are waiting to begin antiretroviral therapy (ART) and for those on ART who have not yet regained immune competence.||Methods: This is a double blind randomised placebo-controlled trial, with an original sample size of 590 HIV positive adults with CD4 counts less than 200 cells/microlitre, not (initially) on ART at enrolment, to be followed for 15 - 33 months. In 2006 the sample size was increased to 1420 to enable us including more patients who are about to start ART. Primary outcome measures are time to invasive cryptococcal disease or mortality attributable to cryptococcal disease. Secondary outcome measures include all cause mortality, time to first episode of symptomatic oro-pharyngeal candidiasis and time to first episode of oesophageal candidiasis. ||Participants are randomised to receive 200 mg fluconazole 3 times per week or placebo. They are routinely seen at 3-monthly intervals and can visit study clinics whenever ill. After enrolment participants are actively referred to ART outlets available in the study area. The project provides referral documentation on clinical and laboratory data to these services in order to facilitate the beginning of ART provision. Participants on ART stop taking trial drug (fluconazole or placebo) once their CD4 count is greater than 200 cells/microlitre.|

Publications

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Namakoola I (2010) Use of nail and oral pigmentation to determine ART eligibility among HIV-infected Ugandan adults. in Tropical medicine & international health : TM & IH

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Sloan DJ (2009) Treatment of cryptococcal meningitis in resource limited settings. in Current opinion in infectious diseases

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Wakeham K (2010) Co-administration of fluconazole increases nevirapine concentrations in HIV-infected Ugandans. in The Journal of antimicrobial chemotherapy

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Wakeham K (2010) Co-administration of fluconazole increases nevirapine concentrations in HIV-infected Ugandans. in The Journal of antimicrobial chemotherapy

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Wakeham K (2010) Symptom burden in HIV-infected adults at time of HIV diagnosis in rural Uganda. in Journal of palliative medicine

 
Description MoH policy on cryptococcal disease
Geographic Reach Africa 
Policy Influence Type Gave evidence to a government review
Impact The MoH has received and discussed trial results. Policymakers at the MoH informed the researchers that they plan to revise current guidelines for HIV care in the light of the trial results.
 
Title crypto trial data base 
Description Data, blood and other biological specimens were collected from about 1500 trial participants. These relate to clinical status and mortality, HIV and cryptococcal infection, haematological parameters, and liver and renal function tests. 
Type Of Material Database/Collection of Data/Biological Samples 
Provided To Others? No  
Impact The research material was used to establish the effectiveness of fluconazole in preventing systemic cryptococcal disease. 
 
Title research clinic 
Description A research clinic suitable for clinical trials was establsihed in Masaka town within the premises of the Regional Hospital. 
Type Of Material Improvements to research infrastructure 
Provided To Others? No  
Impact The clinic is used for other studies; and will be used for a new trial funded by MRC, to commence in 2010. 
 
Title CRYPTOPRO 
Description Fluconazole prophylaxis 
Type Therapeutic Intervention - Drug
Current Stage Of Development Small-scale adoption
Year Development Stage Completed 2010
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Reduction in incidence 
URL http://www.isrctn.com/ISRCTN76481529
 
Description TASO 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Health professionals
Results and Impact Trial results were presented to senior staff and the patient community of The AIDS Support Organisation (TASO) as well as to other local health care providers.

TASO now plans to provide fluconazole prophylaxis to all its eligible clients in Uganda.
Year(s) Of Engagement Activity 2008