- Efavirenz (EFV) remains a good first-line ART option for patients who tolerate DTG poorly, or where DTG is contraindicated or declined.
- EFV 400 mg is non-inferior to EFV 600 mg and offers a somewhat improved side-effect profile. However, it is currently not available in FDC, and has not been well studied in patients receiving RIF-based TB treatment or in pregnant women.
- Rilpivirine (RPV) is another good first-line option, but it is not available in FDC, cannot be co-administered with rifampicin (RIF)-based tuberculosis (TB) treatment, and should not be started in patients with a VL > 100 000 copies/mL.
- Nevirapine (NVP) is no longer recommended for new patients due to its adverse side-effect profile.
- Etravirine (ETR) may be used as part of third-line therapy where appropriate, but is not recommended as a first-line agent.
Overview of non-nucleoside reverse transcriptase inhibitors
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) work by binding irreversibly to HIV’s reverse transcriptase enzyme, which causes a conformational change in the enzyme’s active site and impairs its functioning. The four NNRTIs currently available in southern Africa are efavirenz (EFV), nevirapine (NVP), rilpivirine (RPV) and etravirine (ETR).
Efavirenz (EFV) is available in 600 mg and 400 mg formulations. EFV 600 mg is available in public sector programmes in most countries in southern Africa. There is extensive clinical experience with the formulation, and it is available in FDC. EFV 400 mg demonstrated non-inferior efficacy with moderately improved tolerability in the ENCORE1 study.22 However, there are only limited pharmacokinetics data in pregnant patients, and in patients receiving RIF-based TB treatment. EFV 400 mg is currently also not available in FDC. For these reasons, we do not recommend the routine use of EFV 400 mg in first-line ART. It remains an appropriate choice, however, in selected patients.
EFV frequently causes neuropsychiatric effects in the first few weeks of therapy, typically presenting with insomnia, vivid dreams and dizziness. Both dysphoria and euphoria may occur. Patients starting EFV should be warned about these symptoms, and reassured that they resolve in most patients continuing the drug after the first few weeks, and if not, then an alternative can be substituted. Psychosis may occasionally occur. If the neuropsychiatric effects of EFV are not tolerated, then the patient should be switched to RPV, DTG or lower-dose EFV. Recently, a late-onset encephalopathy syndrome has been linked to EFV.23 This is characterised by a subacute encephalopathy and cerebellar dysfunction, frequently presenting months to years after commencing EFV, and is associated with supratherapeutic EFV levels. Patients who are genetically slow metabolisers of EFV may be predisposed to this syndrome. Two common CYP2B6 polymorphisms linked to slow EFV metabolism have been shown to occur with increased frequency in patients of African descent.24 This predisposition to toxic EFV levels may be further exacerbated in patients of low body weight and in those taking concomitant isoniazid (INH), which inhibits an accessory EFV metabolism pathway via CYP2A6. Patients with a compatible clinical syndrome, in the absence of an alternative cause, should have plasma EFV levels measured and should be switched to a non-EFV-based regimen. Clinical improvement is typically seen within 10–21 days after stopping EFV.
EFV may also cause a drug-induced hepatitis. A subset of these cases appears to occur relatively late, several months or even years after the drug has been initiated.25 It is important that this diagnosis is considered in the differential diagnosis of a subacute hepatitis syndrome. Gynaecomastia can occur with the use of EFV.26 This is not related to lipodystrophy. The onset occurs several months after initiation of ART and it may be bilateral or unilateral. The mechanism appears to be related to oestrogen receptor activation in breast tissue by EFV.27 It is important to exclude other common causes of gynaecomastia, such as other medications (including spironolactone, calcium channel blockers and metoclopramide). A serum testosterone test is useful in excluding hypogonadism as a cause. If serum testosterone is low, then other appropriate investigations should be done to identify the cause and manage accordingly; if serum testosterone is normal, then EFV should be substituted, bearing in mind the general principles of single-drug substitutions (patients who are virologically suppressed should be switched to DTG or RPV). Resolution of gynaecomastia is generally slow, taking months, and may be incomplete in a small percentage.28 It is therefore important to manage the expectations of the patient in this regard.
Another option in first-line ART is rilpivirine (RPV) – a second-generation NNRTI. RPV is inexpensive, but not currently available in FDC in the region. An important drawback is that it should not be started in a patient with a VL > 100 000 copies/mL, as it is inferior to EFV in such patients.29 RPV has a lower incidence of neuropsychiatric side-effects and rashes than EFV.30 There are several important drug-drug interactions with RPV. Among other considerations, RPV cannot be co-administered with RIF or proton-pump inhibitors (PPIs). Histamine-2 (H2)-receptor antagonists need to be administered 12 hours before or 4 hours after taking RPV. RPV should be taken with food to increase absorption.
|Common pitfall: Prescribing RPV without first ascertaining the baseline VL. RPV is less efficacious than comparator drugs when VL > 100 000 copies/mL.|
We no longer recommend nevirapine (NVP) use for new patients starting ART due to the severe toxicity that may be associated with its use. In patients currently tolerating NVP, there is no reason to switch treatment due to toxicity concerns, as toxicity characteristically occurs in the first 3 months of NVP treatment and not later. However, switching for the purpose of simplification to a once-daily regimen should be considered, provided there is virological suppression.
Etravirine (ETR) is a second-generation NNRTI that has been studied in treatment-experienced patients rather than in ART-naïve patients. As is seen with RPV, ETR’s activity is not affected by the first-generation NNRTI’s signature K103N resistance mutation.
Rash is common with NNRTIs in the first 6 weeks of therapy; notably more severely and frequently with NVP. If the rash is accompanied by systemic features (e.g. fever, elevated alanine transaminase (ALT) or hepatitis), mucosal involvement or blistering, then the NNRTI should be discontinued immediately and re-challenge must not be performed as these are features of life-threatening reactions. If the rash is mild and occurs without these features, then the NNRTI can be continued and the rash can be treated symptomatically with antihistamines and possibly topical steroids. Systemic steroids should not be used. If there was a severe reaction to EFV or NVP, then we do not recommend switching to RPV or ETR – rather use DTG or a PI.
Dosage and common ADRs of NNRTIs available in southern Africa are described in Table 5.
|Common pitfall: Immediately discontinuing NNRTIs in the case of a mild rash without systemic features. Such rashes often resolve if treatment is continued, although close monitoring is required.|
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|TABLE 5: Dosage and common adverse drug reactions of non-nucleoside reverse transcriptase inhibitors available in southern Africa.|
|Drug||Recommended dosage||Common or severe ADR†|
|EFV||600 mg at night (400 mg at night if < 40 kg)
400 mg dose can also be used in patients > 40 kg
|CNS symptoms (vivid dreams, problems with concentration, dizziness, confusion, mood disturbance, psychosis, late-onset encephalopathy), rash, hepatitis, gynaecomastia|
|NVP||200 mg daily for 14 days then 200 mg 12-hourly||Rash, hepatitis|
|RPV||25 mg daily with food||Rash, hepatitis, CNS symptoms (all uncommon)|
|ETR‡||200 mg 12-hourly||Rash, hepatitis (both uncommon)|
ADR, adverse drug reaction; CNS, central nervous system; EFV, efavirenz; ETR, etravirine; NNRTI, non-nucleoside reverse transcriptase inhibitors; NVP, nevirapine; RPV, rilpivirine.
†, Life-threatening reactions are indicated in bold.