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
Immediate ART initiation is not recommended in HIV-infected patients with cryptococcal meningitis due to the high risk of IRIS, which may be life-threatening
Notes and Remarks
- 1)In developing these recommendations, the Guideline Development Group placed high value on earlier initiation of ART to reduce the high HIV-related mortality in the months prior to ART initiation, particularly in sub-Saharan Africa, balanced against the more frequent (estimated 15% to 30% of patients with CM) and life-threatening risk of intracranial cryptococcal IRIS. Other considerations with earlier initiation of ART are the higher pill burden, and potential drug interactions with high-dose fluconazole.
- 2)There is a high rate of loss to follow up in patients with cryptococcal disease discharged from hospital, and poor linkages with outpatient ART services. Therefore, PITC and referral for HIV care services should be undertaken as soon as appropriate following diagnosis of cryptococcal disease, and at least before hospital discharge.
- 3)The optimal timing of ART after cryptococcal meningitis is unclear, with conflicting evidence from two two RCTs with very different study designs. In one trial, there was a reduction in AIDS progression or deaths when ART was initiated at 14 days versus a median of 45 days following an OI. Although it was not powered to examine the impact of ART timing in specific OIs, a non-significant trend favoured earlier ART in patients with CM who were treated with amphotericin B. In a second small trial, there was increased mortality in adult patients given very early (less than 72 hours) versus delayed (10 weeks) ART following fluconazole induction therapy, but this trial stopped prematurely and had several methodological limitations. Therefore, in contrast to the strong evidence for a mortality reduction with early ART initiation in patients with TB and a CD4 count less than 50 cells/mm3, immediate ART initiation is not recommended in patients with CM because of the potentially high risk of life-threatening intracranial IRIS, especially with fluconazolebased regimens.
- 4)The Guideline Development Group made a conditional recommendation to defer ART initiation for 2-4 weeks (following an amphotericin B-based induction regimen), or longer at 4-6 weeks (following a fluconazole-based induction regimen), based on a lower rate and longer time to achieve CSF fungal clearance with fluconazole compared to amphotericin B in two observational studies.
- 5)In patients with non-meningeal cryptococcal disease, where the risk of life-threatening IRIS is low, the Guideline Development Group recommended even earlier initiation of ART therapy (after two weeks of amphotericin B-based induction, or 4 weeks of highdose oral fluconazole). A large RCT on the optimal timing of ART initiation in CM is ongoing in Uganda and South Africa, with results expected in 2014.
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