WHO Guidelines for management of cryptococcal disease in HIV-infected patients

WHO has released its new Guidelines for the diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children. Cryptococcal disease is an opportunistic infection that occurs primarily among people with advanced HIV disease and the most common presentation of which is cryptococcal meningitis.The disease accounts for an estimated 15% of all AIDS-related deaths globally.

These guidelines provide recommendations and good practice guidance on the optimal approach to diagnosing cryptococcal meningitis, strategies for preventing invasive cryptococcal disease through cryptococcal antigen screening and pre-emptive fluconazole therapy, treating cryptococcal meningitis with combination antifungal therapy regimens, preventing, monitoring and managing amphotericin B drug toxicity, recommendations against adjunctive therapy with systemic corticosteroids and recommendations on the timing of antiretroviral therapy (ART) initiation.

Key Recommendations

1. For adults, adolescents and children living with HIV suspected of having a first episode of cryptococcal meningitis, prompt lumbar puncture with measurement of cerebrospinal fluid (CSF) opening pressure and rapid cryptococcal antigen assay is recommended as the preferred diagnostic approach.

A. In settings with ready access to and no contraindication for lumbar puncture:

i) If both access to a cryptococcal antigen assay (either lateral flow assay or latex agglutination assay) and rapid results (less than 24 hours) are available:
Lumbar puncture with rapid CSF cryptococcal antigen assay is the preferred diagnostic approach. (Strong recommendation, moderate-certainty evidence for adults and adolescents; low-certainty evidence for children)
ii) If access to a cryptococcal antigen assay is not available and/or rapid results are not available:
Lumbar puncture with CSF India ink test examination is the preferred diagnostic approach.
(Strong recommendation, moderate-certainty evidence for adults and adolescents; low-certainty evidence for children)

B. In settings without immediate access to lumbar puncture or when lumbar
puncture is clinically contraindicated: a
i) If both access to a cryptococcal antigen assay and rapid results (less than 24 hours) are available:
Rapid serum, plasma or whole-blood cryptococcal antigen assays are the preferred diagnostic approaches. (Strong recommendation, moderate-certainty evidence for adults and adolescents; low-certainty evidence for children)
ii) If a cryptococcal antigen assay is not available and/or rapid access to results is not ensured:
Prompt referral for further investigation and treatment as appropriate.

(Strong recommendation, moderate-certainty evidence for adults and adolescents; low-certainty evidence for children) Screeninga for cryptococcal antigen followed by pre-emptive antifungal therapy among cryptococcal antigen–positive people to prevent the development of invasive cryptococcal disease is recommended before initiating or reinitiating ART for adults and adolescents living with HIV who have a CD4 cell count <100 cells/mm3 (strong recommendation; moderate-certainty evidence) and may be considered at a higher CD4 cell count threshold of <200 cells/mm3
(conditional recommendation; moderate certainty evidence).

When cryptococcal antigen screening is not available, fluconazole primary prophylaxis should be given to adults and adolescents living with HIV who have a CD4 cell count <100 cells/mm3 (strong recommendation; moderate-certainty evidence) and may be considered at a higher CD4 cell count threshold of < 200 cells/mm3 (conditional recommendation; moderate-certainty evidence).Screening and primary prophylaxis are not recommended for children, given the low incidence of cryptococcal meningitis in this age group.

Treatment of cryptococcal meningitis

The following is recommended as the preferred induction regimen:
• For adults, adolescents and children, a short-course (one-week) induction regimen with amphotericin B deoxycholate (1.0 mg/kg/day) and flucytosine (100 mg/kg/day, divided into four doses per day) is the preferred option for treating cryptococcal meningitis among people living with HIV (strong recommendation, moderate-certainty evidence for adults, low-certainty evidence for children and adolescents).

The following induction regimens are recommended as alternative options depending
on drug availability:Two weeks of fluconazole (1200 mg daily for adults, 12 mg/kg/day for children and adolescents) + flucytosine (100 mg/kg/day, divided into four doses per day)(strong recommendation, moderate-certainty evidence)

Two weeks of amphotericin B deoxycholate (1.0 mg/kg/day) + fluconazole (1200 mg daily for adults, 12 mg/kg/day for children and adolescents up to a maximum of 800 mg daily) (strong recommendation, moderate-certainty evidence).

Consolidation Fluconazole (800 mg daily for adults, 6–12 mg/kg/day for children and adolescents up to a maximum of 800 mg daily) is recommended for the consolidation phase (for eight weeks following the induction phase) (strong recommendation, low-certainty evidence).
Maintenance (or secondary prophylaxis) Fluconazole (200 mg daily for adults, 6 mg/kg/day for adolescents and children) is recommended for the maintenance phase (strong recommendation, high-certainty evidence).
Routine use of adjunctive corticosteroid therapy during the induction phase is not recommended in treating HIV-associated cryptococcal meningitis among adults, adolescents, and children (strong recommendation, high-certainty evidence for adults and adolescents, moderate-certainty evidence for children).

Immediate ART initiation is not recommended for adults, adolescents and children livingwith HIV who have cryptococcal meningitis because of the risk of increased mortality and should be deferred by 4–6 weeks from the initiation of antifungal treatment.(Strong recommendation, low-certainty evidence for adults and very-low-certainty evidence for children and adolescents)

Preventing, monitoring and managing amphotericin B toxicity

Safe administration of amphotericin B should be given priority and may require referral to a centre with access to a minimum package of preventing, monitoring and managing toxicity. A minimum package of preventing, monitoring and managing toxicity should
be provided to minimize the serious types of amphotericin B–related toxicity, especially hypokalaemia, nephrotoxicity and anaemia (Table 2).

Monitoring for and managing raised intracranial pressure

Monitoring for raised intracranial pressure
Adults, adolescents and children living with HIV with suspected cryptococcal meningitis should have an initial lumbar puncture and an early repeat lumbar puncture with measurement of CSF opening pressure to assess for raised intracranial pressure regardless of the presence of symptoms or signs of raised intracranial pressure.

Managing raised intracranial pressure
• Therapeutic lumbar puncture: relieve pressure by draining a volume sufficient to reduce the CSF pressure to <20 cm H20 or halving the baseline pressure baseline pressure if extremely high.a
• The persistence or recurrence of symptoms or signs of raised intracranial pressure should determine the frequency of repeat therapeutic lumbarpuncture. For people with persistent symptoms of intracranial pressure, repeatdaily therapeutic lumbar puncture (with measurement of CSF opening pressure where available) and CSF drainage, if required, are recommended until the symptoms resolve or the opening pressure is normal for at least two days.

Monitoring treatment response

• Clinical response (including resolution or recurrence of fever, headache and symptoms or signs of raised intracranial pressure) should be assessed daily during the initial two weeks of induction therapy.
• Among people with evidence of a sustained clinical response, routine followup lumbar puncture after completing induction treatment to assess antifungal treatment response (CSF fungal culture and CSF cryptococcal antigen) or serum or plasma cryptococcal antigen is not advised in low- and middle income countries.

Managing relapse

For people who present with cryptococcal meningitis relapse, the following steps are advised:
• Start or restart induction treatment according to the recommendations for induction treatment in section 3.3.
• Manage raised intracranial pressure with therapeutic lumbar puncture
(see section 3.6.1).
• Reinforce adherence.
• If ART has not already started, initiating ART after 4–6 weeks of optimal antifungal therapy is recommended (see section 3.7 on recommendations on the timing of ART initiation).

Implementation of the new WHO guidelines will help improve diagnosis, prevention and treatment of one of the most common opportunistic infections among people with advanced HIV disease. It will also reduce the rates of HIV-related mortality – globally and particularly in Africa.