ART Guidelines

ART Guidelines

Please review the disclaimer before proceeding with these guidelines



  • ×
    /r ritonavir-boosted
    3TC lamivudine
    ABC abacavir
    ADR adverse drug reaction
    AKI acute kidney injury
    ALT alanine transaminase
    ART antiretroviral therapy
    ARV antiretroviral
    AST aspartate transaminase
    ATV atazanavir
    ATV/r ritonavir-boosted atazanavir
    AZT zidovudine
    bd twice daily
    CD4+ cluster of differentiation 4
    CM cryptococcal meningitis
    CrAg cryptococcal antigen
    CrCl creatinine clearance rate
    CSF cerebrospinal fluid
    CTX cotrimoxazole
    CVS cardiovascular
    d4T stavudine
    DILI drug-induced liver injury
    DNA deoxyribonucleic acid
    DOR doravirine
    DRV darunavir
    DRV/r ritonavir-boosted darunavir
    DTG dolutegravir
    eGFR estimated glomerular filtration rate
    ELISA enzyme-linked immunosorbent assay
    ETR etravirine
    FBC full blood count
    FDC fixed dose combination
    FTC emtricitabine
    GI gastrointestinal
    Hb haemoglobin
    HBsAg hepatitis B surface antigen
    HBV hepatitis B virus
    HIV human immunodeficiency virus
    ICU intensive care unit
    InSTI integrase strand transfer inhibitor
    IPT isoniazid preventive therapy
    LAM lipoarabinomannan
    LDL-C low-density lipoprotein cholesterol
    LP lumbar puncture
    LPV lopinavir
    LPV/r ritonavir-boosted lopinavir
    MDRD modification of diet in renal disease
    MTCT mother-to-child transmission of HIV
    MVC maraviroc
    NGT nasogastric tube
    NNRTI non-nucleoside reverse transcriptase inhibitor
    NRTI nucleoside reverse transcriptase inhibitor
    NTDs neural-tube defects
    NtRTI nucleotide reverse transcriptase inhibitor
    NVP nevirapine
    OI opportunistic infection
    PCR polymerase chain reaction
    PI protease inhibitor
    PI/r ritonavir-boosted protease inhibitor
    PMTCT prevention of mother-to-child transmission of HIV
    PPIs proton pump inhibitors
    PrEP pre-exposure prophylaxis
    PWH people with HIV
    RAL raltegravir
    RCTs randomised controlled trials
    RIF rifampicin
    RFB rifabutin
    RNA ribonucleic acid
    RPV rilpivirine
    RTV or /r ritonavir
    sCr serum creatinine
    sCrAg serum cryptococcal antigen
    TAF tenofovir alafenamide
    TAM thymidine analogue mutation
    TB tuberculosis
    TB-IRIS tuberculosis immune reconstitution inflammatory syndrome
    TBM tuberculosis meningitis
    TC total cholesterol
    TDF tenofovir disoproxil fumarate
    TG triglycerides
    TST tuberculin skin test
    ULN upper limit of normal
    VL viral load
    VTP vertical transmission prevention of HIV
    WHO World Health Organization

            Key points
    • Efavirenz (EFV) remains an ART option for patients who tolerate DTG poorly, or where DTG is contraindicated or declined.
    • EFV 400 mg is virologically non-inferior to EFV 600 mg and offers a somewhat improved side-effect profile. The 400 mg formulation is preferred in most instances, except for those patients receiving rifampicin (RIF)- based tuberculosis (TB) treatment, to whom 600 mg should be given.
    • Rilpivirine (RPV) is another alternative but cannot be co-administered with RIF-based TB treatment, and should not be started in patients with a VL > 100 000 copies/mL.
    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).

    Individual non-nucleoside reverse transcriptase inhibitors

    Efavirenz (EFV) is available in 600 mg and 400 mg formulations, and both are now available as fixed dose combinations (FDC). EFV 600 mg is available in public sector programmes in South Africa and there is extensive clinical experience with the formulation. EFV 400 mg demonstrated non-inferior efficacy with moderately improved tolerability in the ENCORE1 study. 39 However, there are only limited pharmacokinetic data in pregnant patients, and in patients receiving RIF-based tuberculosis treatment. For most patients requiring EFV, EFV 400mg should be used unless they are also on RIF-based tuberculosis treatment, in which case EFV 600mg should be used. 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. EFV may also cause a skin rash, which is usually mild. 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 but, if not, an alternative can be substituted. Psychosis and Stevens-Johnson syndrome may occasionally occur. If the neuropsychiatric effects of EFV are not tolerated, then drug switching is recommended.

    Recently, a late-onset encephalopathy syndrome has been linked to EFV. 40 This is characterised by a subacute encephalopathy and cerebellar dysfunction including ataxia, 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. 41 This predisposition to toxic EFV levels may be further exacerbated in patients of low body weight and in those taking concomitant isoniazid, 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 in the interim. Clinical improvement is typically seen within 10–21 days after stopping EFV.

    EFV may also cause drug-induced hepatitis. A subset of these cases appears to occur relatively late, several months or even years after the drug has been initiated. 42 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. 43 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. 44 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 be managed accordingly. If serum testosterone is normal, then EFV should be substituted for another drug. Resolution of gynaecomastia is generally slow, taking months, and may be incomplete in a small percentage. 45 It is therefore important to manage the expectations of the patient in this regard.

    Pills Image

    Another option in first-line ART is rilpivirine (RPV), a second-generation NNRTI . RPV is inexpensive and is available in fixed dose combination (FDC) combination on its own or as a with DTG. An important drawback is that it should not be started in patients with a VL > 100 000 copies/mL, as it is inferior to EFV in such patients. 46 RPV has a lower incidence of neuropsychiatric side-effects and rashes than EFV. 47 There are several important drug-drug interactions with RPV. Among other considerations, RPV cannot be co-administered with RIF or protonpump inhibitors (PPIs). H2-receptor antagonists need to be administered 12 hours before or 4 hours after taking RPV. RPV must be taken with food to increase absorption.

    Common pitfalls:
    • Prescribing RPV without first checking baseline VL. RPV is less efficacious than comparator drugs when VL > 100 000 copies/mL.
    • Forgetting that RPV needs to be taken with food.

    We do not recommend nevirapine (NVP) for new patients starting ART due to the severe toxicity that may be associated with its use. Although toxicity after the first 3 months of NVP treatment is unlikely, we also strongly recommend switching all patients currently on NPV to a more robust once-daily regimen.


    Etravirine (ETR) is a second-generation NNRTI that has been studied in treatment-experienced patients rather than in ART-naïve patients. 48 As is seen with RPV, ETR’s activity is not affected by the first generation NNRTI’s signature K103N resistance mutation.

    Hypersensitivity with non-nucleoside reverse transcriptase inhibitors

    Development of a rash is common in the first 6 weeks of therapy with an NNRTI; 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 be avoided 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 protease inhibitor (PI). Dosage and common adverse drug reactions of nonnucleoside reverse transcriptase inhibitors available in Southern Africa are described in Table 5.

    Common pitfall: Immediately discontinuing an NNRTI in the case of a mild rash without systemic features Such rashes often resolve if treatment is continued, though close monitoring is required.

    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; RIF, rifampicin.
    †, Life-threatening reactions are indicated in bold; ‡, NNRTI combinations to be avoided due to drug interactions include: (i) ETR + ATV/r and (ii)
    ETR + DTG unless a boosted PI is also used in the combination.