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Page 7 of 39 Guideline

Overview of non-nucleoside reverse bilateral or unilateral. The mechanism appears to be related to
transcriptase inhibitors oestrogen receptor activation in breast tissue by EFV. It is
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important to exclude other common causes of gynaecomastia,
Non-nucleoside reverse transcriptase inhibitors work by such as other medications (including spironolactone, calcium
binding irreversibly to HIV’s reverse transcriptase enzyme, channel blockers and metoclopramide). A serum testosterone
which causes a conformational change in the enzyme’s active test is useful in excluding hypogonadism as a possible cause. If
site and impairs its functioning. The four NNRTIs currently serum testosterone is low, then other appropriate investigations
available in southern Africa are EFV, NVP, RPV and ETR.
should be carried out to identify the cause and manage
accordingly; if serum testosterone is normal, then EFV should
Individual non-nucleoside reverse transcriptase be substituted, bearing in mind the general principles of single-
inhibitors drug substitutions (patients who are virologically suppressed
Efavirenz should be switched to DTG or RPV). Resolution of gynaecomastia
Efavirenz is available in 600 mg and 400 mg formulations: is generally slow, taking months, and may be incomplete in a
Efavirenz 600 mg is available in public sector programmes in small percentage of patients. It is therefore important to
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most countries in southern Africa. There is extensive clinical manage the expectations of the patient in this regard.
experience with the formulation, and it is available in FDC.
Efavirenz 400 mg showed non-inferior efficacy with Rilpivirine
moderately improved tolerability in the ENCORE1 study. Another option in first-line ART is RPV, a second-generation
22
However, there are only limited pharmacokinetics data in NNRTI: Rilpivirine is inexpensive, but not currently available
pregnant patients, and in patients receiving RIF-based TB in FDC in the region. An important drawback is that it should
treatment. Efavirenz 400 mg is currently also not available in not be started in a patient with a VL > 100 000 copies/mL, as
FDC. For these reasons, we do not recommend the routine it is inferior to EFV in such patients. Rilpivirine has a lower
29
use of EFV 400 mg in first-line ART. It remains an appropriate incidence of neuropsychiatric side effects and rashes than
choice, however, in selected patients.
EFV. There are several important drug–drug interactions
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with RPV. Amongst other considerations, RPV cannot be
Efavirenz frequently causes neuropsychiatric effects in the co-administered with RIF or proton pump inhibitors (PPIs).
first few weeks of therapy, typically presenting with insomnia, Histamine-2-receptor antagonists need to be administered
vivid dreams and dizziness. Both dysphoria and euphoria 12 h before or 4 h after taking RPV. Rilpivirine should be
may occur. Patients starting on EFV should be warned about taken with food to increase absorption.
these symptoms and should be reassured that the symptoms
usually resolve within the first few weeks, and if not, then an ° Common pitfall: Prescribing RPV without first
alternative can be substituted. Psychosis may occasionally checking baseline VL. Rilpivirine is less efficacious than
occur. If the neuropsychiatric effects of EFV are not tolerated, comparator drugs when VL is > 100 000 copies/mL.
then the patient should be switched to RPV, DTG or lower-
dose EFV. Recently, a late-onset encephalopathy syndrome Nevirapine
has been linked to EFV. This is characterised by a subacute
23
encephalopathy and cerebellar dysfunction, frequently We no longer recommend NVP use for new patients starting
presenting months to years after commencing EFV, and is ART because of the severe toxicity that may be associated
associated with supratherapeutic EFV levels. Patients who with its use: In patients currently tolerating NVP, there is
are genetically slow metabolisers of EFV may be predisposed no reason to switch treatment because of toxicity concerns,
to this syndrome. Two common CYP2B6 polymorphisms as toxicity characteristically occurs in the first 3 months of
linked to slow EFV metabolism have been shown to occur NVP treatment and not later. However, switching for the
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with increased frequency in patients of African descent. This purpose of simplification to a once-daily regimen should be
predisposition to toxic EFV levels may be further exacerbated considered, provided that there is virological suppression.
in patients of low body weight and in those taking concomitant
isoniazid, which inhibits an accessory EFV metabolism Etravirine
pathway via CYP2A6. Patients with a compatible clinical
syndrome, in the absence of an alternative cause, should have Etravirine is a second-generation NNRTI that has been
plasma EFV levels measured and should be switched to a studied in treatment-experienced patients rather than in
non-EFV-based regimen. Clinical improvement is typically ART-naive patients: As seen with RPV, the activity of ETR is
seen within 10–21 days after stopping EFV. not affected by the first-generation NNRTI’s signature K103N
resistance mutation.
Efavirenz may also cause a drug-induced hepatitis. A subset of Hypersensitivity with non-nucleoside reverse
these cases appears to occur relatively late, several months or
even years after the drug has been initiated. It is important that transcriptase inhibitors
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this diagnosis is considered in the differential diagnosis of a Rash is common with NNRTIs in the first 6 weeks of therapy,
subacute hepatitis syndrome. Gynaecomastia can occur with notably more severely and frequently with NVP. If the rash is
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the use of EFV. This is not related to lipodystrophy. The onset accompanied by systemic features (e.g. fever, elevated alanine
occurs several months after initiation of ART and it may be transaminase [ALT] or hepatitis), mucosal involvement or

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