Page 16 - SAHCS HIVMed Journal Vol 20 No 1 2019

Page 3 of 16 Guideline

Detailed recommendations per Recommendation 3. In the latter group, ART should be
commenced 4–6 weeks after the introduction of antifungal
Who to screen?
therapy. Patients in whom CM is ruled out by LP (a negative
HIV-seropositive adults and adolescents (≥ 10 years) with a CSF CrAg test is the most rapid method to establish this)
CD4 count < 200 cells/µL are recommended to be screened should be given oral fluconazole alone as induction therapy
for cryptococcal antigenaemia. If screening is initiated by a (adults: 1200 mg for 2 weeks). This is followed by standard
clinician (medical practitioner or a nurse trained to initiate consolidation and maintenance treatment regimens as per
ART) and not performed reflexively in the laboratory, the Recommendation 3. In these blood CrAg-positive/CSF
expert panel recommends that screening must be restricted to CrAg-negative patients, ART may be commenced
adults and adolescents initiating ART for the first time, immediately, with the caveat that there is no published
switching after treatment failure or re-initiating ART (after an evidence for this recommendation. Adolescents and
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episode of interruption that was > 3 months) with a CD4 children should receive fluconazole 12 mg/kg/day (to a
count < 200 cells/µL and no prior CM. Although adults or maximum of 800 mg per day) for 2 weeks followed by
adolescents with a CD4 count < 200 cells/µL who are virally standard consolidation and maintenance treatment. The
suppressed on ART may also be at risk of cryptococcal timing of ART initiation should be the same as adults.
disease, there is insufficient current evidence to routinely
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recommend screening in this group. There are also insufficient Patients who decline an LP can be stratified according to the
data to recommend routine cryptococcal screening of HIV- presence or absence of meningitis symptoms (Figure 1),
infected children (< 10 years) in whom the incidence of CM is although this approach is now recognised to be suboptimal.
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much lower. Even though data for adolescents are limited, Patients with headache, nausea, vomiting or other signs of
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the WHO currently recommends screening for adolescents. CM should be treated as such (as per Recommendation 3),
South African data indicate an increasing incidence of CM whereas those without symptoms can be treated with
from the age of 10 years onwards. 15 fluconazole alone, as for patients in whom CM has been
excluded. However, this approach will result in some cases of
Screening strategies asymptomatic or subclinical CM being missed. If a screening
With reflexive laboratory CrAg screening, remnant blood blood CrAg titre is available (this is not routinely performed
samples (submitted to the laboratory for CD4 testing) are in South Africa’s national CrAg screening programme),
tested automatically for CrAg below a specified CD4 threshold. patients with CrAg titres > 160 may be considered at high
This approach is superior to clinician-initiated screening risk of CM or cryptococcal disease-related death. 20,21 Such
(where clinicians specifically request a blood CrAg test) in patients should be carefully monitored for CM signs/
terms of screening coverage. A South African modelling symptoms or considered for empirical CM treatment.
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study comparing the two strategies and using a CD4 threshold Community adherence support is recommended for all
of < 100 cells/µL demonstrated that reflex screening was more patients who screen CrAg-positive and are followed up as
cost-effective and saved more lives. Although the CrAg latex outpatients, particularly among those who decline an LP. 5
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agglutination (LA) test format has been more extensively
evaluated for the diagnosis of cryptococcal disease, a rapid Management of a positive blood cryptococcal antigen
CrAg lateral flow assay is simpler to perform on blood samples result obtained after antiretroviral treatment initiation
and more accurate. The National Health Laboratory Service Current same-day HIV test-and-treat strategies mean that
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(NHLS) expanded its reflex laboratory CrAg screening service some patients may start ART before a positive reflex blood
across South Africa in October 2016. Between October 2016 CrAg result is received. Given the increased risk of mortality
6
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and March 2019, more than 600 000 persons were screened, associated with early ART in CM, the panel recommends
with a CrAg+ prevalence of 5.7% (N.P. Govender, pers. comm., immediate referral for LP and CSF analysis in all patients
02 September 2019, National Institute for Communicable with a positive blood CrAg test who initiated ART in the 4
Diseases). However, the real-world effectiveness of this screen- weeks prior to the CrAg test. Among patients with a negative
and-treat strategy in terms of impact on mortality has yet to be CSF CrAg test (i.e. in whom CM is excluded), ART can be
determined. The laboratory turnaround time is very short for continued and fluconazole pre-emptive therapy should be
both CD4 count and reflex CrAg screening test results; initiated. Among patients on a new ART regimen with a
however, initiation of ART should not be unnecessarily delayed positive CSF CrAg test (i.e. a new diagnosis of CM), data
while awaiting CrAg test results in patients with advanced suggest that mortality may be increased if CM is diagnosed
HIV disease who have no clinical features of meningitis. in the first 4 weeks of ART, possibly mediated through
a mechanism of unmasking immune reconstitution
Management of cryptococcal antigen-positive patients inflammatory syndrome (IRIS). Not all studies have
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without previous cryptococcal meningitis demonstrated this and we do not know if ART interruption
All patients who screen CrAg-positive for the first time would reduce this mortality risk. Potential harms of ART
should have an LP performed. The absence of symptoms of interruption include HIV resistance (more likely with
meningitis does not exclude CM: approximately one in three NNRTI-based regimens but less likely with dolutegravir-
patients with asymptomatic cryptococcal antigenaemia based regimens) and the risk of HIV disease progression and
has concurrent CM. CrAg-positive patients who are other opportunistic infections. The panel thought that there
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subsequently identified as having CM should be managed as was clinical equipoise for the decision whether to continue or

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