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Page 33 of 39 Guideline

other cardiovascular risk factors, a threshold of total ÿ Corticosteroids have been shown to reduce morbidity
cholesterol > 7.5 mmol/L (or LDL cholesterol > 5.0 mmol/L) and improve symptoms in paradoxical TB-IRIS.
should be used for initiating statin therapy, and the patient
should be referred to a lipid clinic for investigation if feasible. Approximately 10% – 20% of patients who start ART with
In patients with cardiovascular risk factors (e.g. smoking, advanced immunosuppression experience clinical
diabetes and hypertension), decisions should be made using deterioration during the first few months because of IRIS.
the Framingham heart disease risk score. All patients with Most presentations of IRIS occur within the first 3 months of
established atherosclerotic disease (coronary, cerebral or ART. Two forms are recognised:
peripheral) or familial hypercholesterolaemia should be
started on statin treatment. In addition, type 2 diabetics • Unmasking IRIS occurs in patients who have an
should also be started on a statin treatment if they have unrecognised OI when ART is initiated, and who then
chronic kidney disease, or if they are older than 40 years of present with exaggerated inflammatory features of that
age (or have had diabetes for more than 10 years) and have infection during early ART because of it being ‘unmasked’
one or more additional cardiovascular risk factors. 91 by recovering immunity.
• Paradoxical IRIS occurs in patients who are being treated
Many statins have interactions with PIs that can lead to for an OI when they start ART, but who develop an
potentially toxic statin concentrations, with the exception of immune-mediated worsening or recurrence of features of
pravastatin and fluvastatin. Atorvastatin concentrations are that infection after starting ART.
significantly raised by PIs, but low doses (maximum 10 mg
daily) can be used with monitoring for symptoms of myalgia. Immune reconstitution inflammatory syndrome is most
Lovastatin and simvastatin should not be co-administered frequently described in association with TB and CM. Skin
with PIs, as their concentrations are dramatically increased, conditions such as molluscum contagiosum and Kaposi’s
and severe rhabdomyolysis has been reported. We also sarcoma may also worsen because of IRIS. The diagnosis of
advise against the use of rosuvastatin with PIs because of a IRIS can be difficult, mainly because there is no confirmatory
complex drug–drug interaction; PIs increase the plasma diagnostic test. Diagnosis relies on recognition of the
concentrations of rosuvastatin whilst reducing their efficacy characteristic clinical presentation, ensuring that OIs are
in the liver. correctly diagnosed, and excluding alternative causes of
° Common pitfalls: deterioration, such as drug resistance (e.g. multidrug-
° Not routinely assessing lipids whilst the patient is resistant TB). Case definitions for TB and cryptococcal IRIS
receiving PI-based ART. have been published. 92,93 It is important to ensure that the
° Failure to recognise that many statins have interactions underlying OI is treated appropriately. Antiretroviral therapy
with PIs that lead to toxic statin concentrations. should be continued, unless the IRIS is life-threatening
° Monitoring of LDL-C in patients on a high-dose (e.g. neurological involvement in TB-IRIS with depressed
statin for secondary prevention. Such monitoring is level of consciousness). Corticosteroids have been shown to
not necessary. reduce morbidity and improve symptoms in paradoxical TB-
IRIS, and can be used in mycobacterial and fungal forms of
94
26. Immune reconstitution IRIS when other causes of deterioration have been excluded,
inflammatory syndrome and particularly when IRIS features are severe.
Key points For paradoxical TB-IRIS, prednisone can be commenced at a
dose of 1.5 mg/kg/day and weaned over 4 weeks, but a
ÿ Approximately 10% – 20% of patients who start ART with
advanced immunosuppression experience IRIS in the longer course may be required if symptoms recur on
95
first few months of treatment. weaning. Steroids should not be used in patients with
ÿ Two forms of IRIS have been recognised, namely Kaposi’s sarcoma.
unmasking and paradoxical IRIS. ° Common pitfall: Using steroids in patients with
ÿ Immune reconstitution inflammatory syndrome is most Kaposi’s sarcoma.
frequently described in association with TB and CM.
ÿ Integrase strand transfer inhibitors are not associated Prophylactic prednisone
with an increased risk of TB-IRIS in clinical trials.
ÿ Early ART initiation (defined as 1–4 weeks after anti- Key points
tuberculous therapy) doubles the risk of TB-IRIS compared ÿ Patients with active TB and who are improving on TB
with late ART initiation (defined as 8–12 weeks after anti- therapy with a CD4 count ≤ 100 cells/μL upon starting
+
tuberculous therapy), but ART should not be delayed for ART can be initiated on prednisone 40 mg daily for 14 days,
this reason in patients with CD4 < 50 cells/μL. followed by 20 mg daily for 14 days to prevent paradoxical
+
ÿ There is no confirmatory diagnostic test for IRIS. TB-IRIS.
ÿ In most instances, ART is continued in cases of IRIS, unless ÿ The use of prednisone in this context is not associated
IRIS is life-threatening (e.g. neurological involvement in with high risk of severe infections, cancers or adverse
TB-IRIS with depressed level of consciousness). events.

http://www.sajhivmed.org.za 51 Open Access