Dr Parkes-Ratanshi believes the quality of care provided in this research setting may have resulted in an understatement of the effect of fluconazole prophylaxis on mortality. For instance “overall, in this study, the rate of crytococcal infection was low. One reason was that we excluded those people who were CrAg positive at the beginning of the study,” she said.
However, most settings in sub-Saharan Africa do not have the capacity to screen all patients (without symptoms) for CrAg, so the rates of invasive cryptococcal disease would normally be higher. In addition, the study participants had better access to rapid diagnosis and optimal treatment, including access to ART. So she believes that the effect of fluconazole prophylaxis is potentially greater and that it “is likely to reduce mortality in patients who are not yet on ART. However, the benefit also extends to those in the first few months on ART before significant improvements in immune status,” she said.
The study makes the evidence base for the current WHO fluconazole prophylaxis recommendation considerably stronger, and many of the often cited reasons for not implementing fluconazole prophylaxis as a routine intervention did not appear to be an issue in this low resourced setting. Critically, it was safe in this population and as a prophylactic measure, resistance was not a major issue in this large cohort. “We didn’t see any resistance in our patients with cryptococcal disease,” said Dr Parkes-Ratanshi. “We haven’t yet gotten the drug sensitivities for candida, but in the clinical setting, there are very few cases of recurrent candida, and we have not found very resistant candida though we are waiting for the sensitivities.”
The fact that fluconazole offered benefit beyond ART is important. Some regional guidelines have quite rightly stated that ART is the most effective preventive measure for cryptococcal disease and that access to ART should be prioritised over introducing fluconazole prophylaxis. But this may be a false dichotomy if fluconazole can easily delivered in a programmatic setting while someone is being prepared to take ART: “It is safe and simple to administer. It doesn’t have to be given by a doctor; it can be given by other healthcare workers; and it can be given at peripheral health centres where there may be no access to ART, certainly no CD4 cell count testing and monitoring for ART,” said Dr Parkes-Ratanshi. Furthermore, it is a time-limited intervention in those starting ART, with a median duration of treatment of about five months.
Of note, a late breaker study presented by Dr Azure Makadzange of the University of Washington, Seattle, and the University of Zimbabwe, Harare, during the same session of the conference, reported a very high rate of death (62%) in people with cryptococcal meningitis treated with high-dose fluconazole (which is the only available option in much of Africa) regardless of whether they started ART or not. In fact, the risk of death was more than twice as high in people who received early versus deferred ART (before finishing their course of fluconazole as treatment). There was much debate about the study’s findings, which seem to contradict other reports, but it is important to note that most of these deaths occurred early on ART, most likely due to IRIS - which fluconazole prophylaxis before ART could possibly prevent.
However, many programmes are still having trouble supplying cotrimoxazole, a clearly life-saving intervention, despite its low cost and widespread availability. Fluconazole is a much more expensive drug. Although fluconazole is made available by Pfizer free of charge to governmental and non-governmental organisations to treat severe AIDS-related fungal infections in less developed countries, it is not clear that the company would be willing to expand access to include its use for prophylaxis. So the inclusion of fluconazole as part of the basic package of care may be limited to countries with access to low-cost, generic formulations of the drug.