Bibliographic Info
GuidelineRapid advice : diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children
Year of Publication2011
Issuing InstitutionWorld Health Organization
Recommendation
Status
Maintained
Recommended against
Conditional
Certainty of evidence
Low
The use of routine CrAg screening in ART-naive adolescents and children with pre-emptive antifungal therapy if CrAG positive, prior to ART initiation is not recommended
Notes and Remarks
- 1)There is a high incidence of cryptococcal meningitis (CM) and mortality before ART initiation, and at least a third of all cases of CM now present after ART initiation. In developing these recommendations, the Guideline Development Group placed high value on prevention of cryptococcal disease, as well as early detection to prevent the development of severe disease and mortality before and after ART initiation.
- 2)The Guideline Development Group recognised that earlier initiation of ART at a CD4 cell count of 350 cells/mm3 in accordance with 2010 WHO guidelines remains the most important preventive strategy to reduce the incidence of cryptococcal infection and associated high mortality.
- 3)The Guideline Development Group recommended against the routine use of primary fluconazole prophylaxis to prevent cryptococcal disease in all patients with a low CD4 count prior to ART, unless a prolonged delay in ART initiation was likely. Five RCTs have shown that azole prophylaxis reduces the incidence of cryptococcal disease (most patients had a CD4 count less than 150 cells/mm3), but there was no clear impact on overall survival, with the exception of one study from Thailand. A further trial of fluconazole prophylaxis in CrAg negative patients with a CD4 count less than 200 cells/mm3 again showed a significant reduction in the risk of cryptococcal disease, but not on all-cause survival. The recommendation was therefore based on the lack of consistent survival benefit associated with routine prophylaxis; the observation that the majority of patients (greater than 90%) even with advanced immunodeficiency are CrAg-negative, and at low risk of developing cryptococcal meningitis unless ART is delayed; the large number of patients that would require prophylaxis and associated costs; the risk of prophylaxis providing inadequate therapy in patients who may have unrecognized active cryptococcal disease; and concerns regarding drug resistance, and the potential for drug interactions and teratogenicity with fluconazole. The Guideline Development Group considered the alternative strategy of serum CrAg screening in ART-naïve patients with low CD4 counts, to identify early on persons at high risk of developing cryptococcal disease, with pre-emptive fluconazole therapy in those CrAg-positive, to prevent cryptococcal disease and associated mortality both before and after ART initiation (including cryptococcal IRIS). There have been three cost effectiveness studies of this “screen and treat” approach in patients with a CD4 count less than 100 cells/ mm3. The cost to prevent one death ranged from $77 to $266, and this approach was estimated to be cost-saving above a CrAg prevalence of 3% in one study against the cost of amphotericin induction therapy. However, further field studies are needed to establish: (i) the feasibility of this “screen and treat” approach and its impact on mortality; (ii) the most cost-effective threshold of prevalence above which a “screen and treatment” programme is cost-effective relative to routine azole prophylaxis in all patients; (iii) the optimal selection of serum CrAg-positive patients who require an LP to rule-out central nervous system (CNS) disease; and (iv) the optimal treatment regimen in those with isolated serum CrAg positivity.
- 4)Therefore, the Guideline Development Group made only a conditional recommendation for programmes to consider the use of a “screen and treat” approach in patients with both a low CD4 count and a high prevalence of cryptococcal infection. Given the low incidence of cryptococcal infection in adolescents and children, a “screen and treat” approach is not recommended in these groups.
- 5)The use of the LFA CrAg point-of-care-test would further facilitate and reduce the costs of a “screen and treat” strategy, especially in settings lacking laboratory support, but only the LA CrAg assay has been evaluated in existing studies. There is a need for prompt evaluation of the utility of LFA as a screening tool in asymptomatic patients across a range of prevalence settings.
Also Featured In
This recommendation also appears in the following guidelines:
Guideline
Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach
Year2016
InstitutionWHO