ART Guidelines

ART Guidelines


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  • ABBREVIATIONS
    /r ritonavir-boosted
    3TC lamivudine
    ABC abacavir
    ADR adverse drug reaction
    AKI acute kidney injury
    ALT alanine transaminase
    ANC antenatal care
    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
    CNS central nervous system
    CrAg cryptococcal antigen
    CrCl creatinine clearance rate
    CSF cerebrospinal fluid
    CTX cotrimoxazole
    d4T stavudine
    ddI didanosine
    DILI drug-induced liver injury
    DNA deoxyribonucleic acid
    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
    FTC emtricitabine
    GI gastrointestinal
    Hb haemoglobin
    HBsAg hepatitis B surface antigen
    HBV hepatitis B virus
    HIV human immunodeficiency virus
    ICU intensive care unit
    INH isoniazid
    INR international normalised ratio
    InSTI integrase strand transfer inhibitor
    IPT isoniazid preventive therapy
    IRIS immune reconstitution inflammatory syndrome
    LAM lipoarabinomannan
    LDL-C low-density lipoprotein cholesterol
    LFT liver function test
    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
    PAS p-aminosalicylic acid
    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
    QTc corrected QT interval
    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
    UDP uridine 5’-diphospho
    ULN upper limit of normal
    VL viral load
    WHO World Health Organization
    WOCP women of childbearing potential








    Protease inhibitor class of antiretroviral drugs
            Key points
     
    • Three protease inhibitor (PI) combinations are recommended in southern Africa: lopinavir (LPV), atazanavir (ATV) or darunavir (DRV), each given with low-dose ritonavir (RTV; indicated as /r) for pharmacokinetic boosting.
    • Ritonavir-boosted lopinavir (LPV/r) is the only PI combination that can be used with RIF-based TB treatment, but the dose of LPV/r must be doubled.
    • ATV and DRV offer a better side-effect profile than LPV.
    • DRV has the highest barrier to resistance of any drug in this class.

    Overview of protease inhibitors

    Protease inhibitors (PIs) are a class of agents that inhibit HIV’s protease enzyme, which is required to cleave HIV’s polyproteins into the final protein products that permit the production of infectious viral particles. Inhibition of this process results in immature, non-infectious virions.

    Three PI combinations are recommended for use in southern Africa: lopinavir (LPV), atazanavir (ATV) and darunavir (DRV), each given with low-dose ritonavir (RTV; indicated as /r).

    RTV is a PI in its own right, but is used principally as a pharmacokinetic ‘booster’. As a potent inhibitor of CYP3A4, its use results in higher drug levels and prolonged half-lives of its companion PI. This allows for lower or less frequent PI dosing, and decreases the chance of viral resistance developing. In rare situations, ATV is used without boosting in first-line therapy. However, this inhibition of CYP3A4, together with several other cytochrome P450 enzymes and P-glycoprotein, results in numerous drug-drug interactions with other medications. See Module 17.

    Common pitfall: Not using a drug interaction checker when prescribing PI-based ART with other medications. Clinically relevant drug-drug interactions are common with this class.

    All PIs may be associated with cardiac conduction abnormalities (especially PR interval prolongation). This seldom results in clinically significant effects, but caution should be taken when co-prescribing other drugs that cause delayed cardiac conduction, such as macrolides or bedaquiline. All PIs are, to some degree, associated with metabolic side-effects. Elevated triglycerides (TG) and elevated low-density lipoprotein cholesterol (LDL-C) are class effects, although these side-effects are more marked with LPV/r than with other PI combinations.31,32

    Dosing and common ADRs of PIs are described in Table 6.
     

    Tip: To best view this table, zoom in or rotate your mobile device into landscape orientation.

    TABLE 6: Dosage and common adverse drug reactions of protease inhibitor drugs available in southern Africa.
    Drug/combination Recommended dosage Common or severe ADR
    ATV/r
    • ATV/r 300 mg/100 mg daily
    • If given with EFV: ATV/r 400/100 mg daily
    Unconjugated hyperbilirubinaemia (visible jaundice in minority of patients), dyslipidaemia (low potential), renal stones (rare), hepatitis (uncommon)
    LPV/r
    • 400 mg/100 mg 12-hourly or
    • 800 mg/200 mg daily (only if PI-naïve)
    GI upset, dyslipidaemia, hepatitis
    DRV/r
    • 600 mg/100 mg 12-hourly
    • 800 mg/100 mg daily (only if no DRV mutations)
    • Consider 400 mg/100 mg daily (only if no DRV mutations)
    GI upset, rash, dyslipidaemia, hepatitis (uncommon)

    Contains sulphonamide moiety (use with caution in patients with sulpha allergy)

    ADR, adverse drug reaction; ATV/r, ritonavir-boosted atazanavir; DRV/r, ritonavir-boosted darunavir; EFV, efavirenz; GI, gastrointestinal; LPV/r, ritonavir-boosted lopinavir; PI, protease inhibitor.

    †, Avoid the combination of ETR + ATV/r (due to drug interaction).


    Individual protease inhibitors
    Lopinavir

    Lopinavir (LPV) is co-formulated with ritonavir (LPV/r, e.g. Aluvia). In general, this twice-daily regimen has greater gastrointestinal (GI) side-effects than other PI combinations, and is associated with a worse metabolic profile. LPV is the only PI that can be used concurrently with RIF-based TB treatment; the LPV/r dose has to be doubled in this instance to 800 mg/200 mg twice daily until 2 weeks after RIF has been stopped (see Module 18).

    Common pitfall: Forgetting to double the dose of LPV/r when starting RIF-based TB treatment.
    Atazanavir

    Atazanavir (ATV) is generally better tolerated than LPV and can be taken once daily. It has important drug interactions with drugs that reduce stomach acidity, such as PPIs. ATV may cause an unconjugated hyperbilirubinaemia as a result of inhibition of the hepatic enzyme uridine-5-diphospho (UDP)-glucuronosyltransferase. Though the hyperbilirubinaemia is harmless and does not reflect a drug-induced liver injury (DILI), a minority of patients will become visibly jaundiced, and this may require switching ART regimens for cosmetic reasons.

    Common pitfall: Mistaking the unconjugated hyperbilirubinaemia sometimes seen with ATV use with a DILI. Conversely, it is equally important to note that ARVs can also cause a true DILI; therefore, a full liver function test (LFT) panel should be checked to distinguish between the two possibilities.
    Darunavir

    Darunavir (DRV) has the highest barrier to resistance of any PI. Mutations selected by ATV or LPV can compromise DRV efficiency. For patients with mutations that confer any degree of resistance to DRV (e.g. I50V, L76V, I84V), the dose should be DRV/r 600 mg/100 mg twice daily. For patients without any DRV mutations, the drug can be taken at a dose of DRV/r 800 mg/100 mg once daily. There is evidence, however, that DRV/r 400 mg/100 mg once daily may be sufficient in this scenario, especially for patients with suppressed VLs at the time of the switch.33,34 Compared with twice-daily dosing, once-daily dosing offers the benefits of reduced pill burden and better side-effect profile. As with ATV, DRV cannot be co-prescribed with RIF-based TB treatment.

    Common pitfall: Prescribing ATV or DRV for patients receiving RIF-based TB treatment. LPV/r is the only PI combination that can be co-prescribed safely with RIF, but the dose of LPV/r must be adjusted as above.