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








    Initial antiretroviral therapy regimens for the previously untreated patient
            Key points
     
    • In ART-naïve patients, the preferred initial regimen is TDF (300 mg) + 3TC (300 mg) (or FTC 200 mg) + DTG (50 mg) daily – available as a once-daily, one-tablet FDC.
    • In patients receiving RIF, DTG dosing needs to be increased to 50 mg twice daily until 2 weeks after stopping RIF.
    • DTG has been associated with a small excess risk of neural-tube defects (NTDs) in women taking the drug at conception – women of childbearing potential (WOCP) should be counselled accordingly.

    Preferred initial antiretroviral therapy regimen

    The preferred initial regimen for previously untreated patients is summarised in Table 11.
     

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    TABLE 11: Preferred initial antiretroviral therapy regimen for previously untreated patients.
    First drug Second drug Third drug
    TDF 300 mg daily 3TC 300 mg daily; or FTC 200 mg daily DTG 50 mg daily

    3TC, lamuvidine; DTG, dolutegravir; FTC, emtricitabine; TDF, tenofovir disoproxil fumarate.


    In patients receiving RIF, the DTG dose needs to be increased to 50 mg twice daily until 2 weeks after stopping RIF. Other drug-drug interactions with DTG are discussed in Module 3 and Module 17.

    Reasons for this preferred regimen are:

    • This combination is available as a once-daily, one-tablet FDC from several suppliers.
    • TDF is preferred over ABC due to: the risk of hypersensitivity reactions with ABC (HLA-B*5701 testing is not widely available in SA); certain studies showing lower VL suppression with ABC when baseline VL > 100 000 copies/mL (although not confirmed in a meta-analysis);6 and cost.
    • 3TC and FTC are regarded as interchangeable in terms of efficacy and safety.
    • DTG is preferred over RAL and RPV because of its higher resistance barrier.63 RAL also requires twice-daily dosing and is not co-formulated in FDC. DTG is preferred over EFV and PIs because superior efficacy and tolerability were demonstrated in clinical trials.12,13
    • There is an increasing prevalence of pre-treatment resistance to NNRTIs in South Africa (> 10% in some studies) which may compromise efficacy of EFV-based regimens.64

    DTG has been associated with a small excess risk of neural-tube defects (NTDs) in women taking the drug at conception (0.3% vs. 0.1% in women on EFV at conception in a large Botswana birth-outcomes surveillance study).18 This risk is lower than originally reported (see Module 19). WOCP should be counselled about this risk and the benefits of DTG, and allowed to make an informed decision regarding the use of DTG and contraception, in line with World Health Organization (WHO) 2019 recommendations. DTG has also been associated with greater weight gain than EFV.21 These issues are discussed in Module 3.

    Alternative initial antiretroviral therapy regimens

    Alternatives regimens for the previously untreated patient are summarised in Table 12.
     

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    TABLE 12: Alternative initial antiretroviral therapy regimens for the previously untreated patient.
    Regimen Notes
    TDF + 3TC (or FTC) + EFV
    • EFV can be used at 600 mg nocte or 400 mg nocte.
    • EFV 400 mg dose is associated with fewer side-effects and less LTFU.
    • EFV 400 mg dose is not available in FDC combination in South Africa.
    • There are insufficient data to recommend the EFV 400 mg dose in pregnant patients and patients receiving RIF although small-cohort studies have suggested that adequate concentrations are achieved in these patients.65,66
    TDF + 3TC (or FTC) + RPV
    • RPV cannot be used in patients receiving RIF.
    • RPV should not be used in initial therapy when baseline VL > 100 000 copies/mL.
    ABC + 3TC + DTG
    • International guidelines recommend HLA-B*5701 testing before prescribing ABC because a negative result rules out the risk of hypersensitivity reaction. However, this genotype is very rare in people of African descent and is thus probably not indicated.
    • In patients of non-African descent, HLA-B*5701 testing should be considered if ABC is to be used, though access to this test is limited in South Africa.

    3TC, lamivudine; ABC, abacavir; DTG, dolutegravir; EFV, efavirenz; FDC, fixed-dose combination; FTC, emtricitabine; LTFU, loss to follow-up; RIF, rifampicin; RPV, rilpivirine; TDF, tenofovir disoproxil fumarate; VL, viral load.


    Alternative initial antiretroviral therapy regimens in specific clinical situations

    There are specific clinical situations in which the preferred combination of TDF + 3TC (or FTC) + DTG cannot be used and the alternatives listed in Table 13 are advised instead.
     

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    TABLE 13: Recommended alternative initial antiretroviral therapy regimens in specific clinical situations where TDF + 3TC (or FTC) + DTG cannot be used.
    Scenario Alternative regimen
    Renal impairment at baseline (CrCl < 50 mL/min) ABC + 3TC + DTG
    Renal impairment develops on TDF ABC + 3TC + DTG
    Patient is intolerant of DTG side-effects TDF + 3TC (or FTC) + EFV (or RPV)
    Pure red cell aplasia develops due to 3TC/FTC TDF + DTG (can then add AZT when Hb has recovered) (or RPV + DTG, provided that VL is suppressed)

    3TC, lamivudine; ABC, abacavir; AZT, zidovudine; CrCl, creatinine clearance rate; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; Hb, haemoglobin; RPV, rilpivirine; TDF, tenofovir disoproxil fumarate; VL, viral load.

    †, In such patients, if renal function subsequently improves (CrCl > 50 mL/min), then they can be switched to TDF + 3TC + DTG.


    If both TDF and ABC are contraindicated and Hb > 8 g/dL, then AZT can be considered as an alternative NRTI.

    Considerations for two-drug first-line regimen of dolutegravir + lamivudine

    This regimen was shown to have an efficacy not inferior to a three-drug regimen in RCTs.67 However, these trials did not include patients with a VL > 500 000 copies/mL and there are no follow-up data beyond 3 years for this regimen. Furthermore, virological suppression was lower in patients with a CD4+ count ≤ 200 cells/μL. Therefore, we do not routinely recommend this regimen unless neither TDF nor ABC can be used. Importantly, HBV must be excluded before considering this regimen as patients with HBV must receive TDF + 3TC (or FTC) to prevent rapid emergence of 3TC resistance. The regimen should also not be used in patients receiving RIF.