ART Guidelines

ART Guidelines

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    /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
    • In ART-naïve patients, the preferred initial regimen is 3TC (300 mg) or (FTC 200 mg) + TDF (300 mg) + DTG (50 mg) daily – available as a once-daily, one-tablet FDC.
    • In patients with renal impairment (eGFR < 50 ml/min/1.73m2), the alternative regimen is 3TC + ABC + DTG.

    Preferred initial antiretroviral therapy regimen

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

    TABLE 11: Preferred initial ART 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, lamivudine; DTG, dolutegravir; FTC, emtricitabine; TDF, tenofovir

    There are no significant interactions between NRTIs and rifampicin (RIF); however, InSTIs, NNRTIs, PIs and maraviroc (MVC) all exhibit drug interactions with RIF. DTG can be used in patients receiving RIF, but a dose adjustment to 50mg twice daily until two weeks after stopping RIF is advised. 88 There is evidence from a Phase 2 trial and an observational cohort that standard DTG dosing with RIF (50mg daily) achieves similar virological suppression to dose adjustment in patients on first-line regimens (see module 17). Other drugdrug interactions with DTG are discussed in module 3 and module 17.

    Patients should be advised to take TLD in the morning given the potential side-effect of insomnia, but if it is more convenient for the patient to take at night this will be tolerated in most patients.

    Reasons for this preferred regimen are:

    • This combination is available as a once-daily, onetablet FDC from several suppliers.
    • TDF is preferred over ABC because the risk of hypersensitivity reactions with ABC (HLA-B*5701 testing is not widely available in SA); studies show lower VL suppression with ABC when baseline VL is > 100 000 copies/mL (although not confirmed in a meta-analysis); 13 and lower 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. 89 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 first-line clinical trials. 19, 20
    • 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. 90
    Alternative initial antiretroviral therapy regimens

    Alternatives regimens for the previously untreated patient are summarised in Table 12.. We only recommend an NNRTI regimen in patients who do not tolerate DTG.

    TABLE 12: 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 (eGFR < 50 mL/min/1.73m2) ABC + 3TC + DTG† or TAF + 3TC + DTG† if eGFR 30-50 mL/min/1.73m2
    Renal impairment develops due to TDF ABC + 3TC + DTG
    Patient is intolerant of DTG side-effects TDF + 3TC (or FTC) + EFV, or TDF + 3TC (or FTC) + RPV
    Pure red cell aplasia develops due to 3TC/FTC TDF + DTG (can consider adding AZT when Hb has recovered) (or RPV + DTG, provided 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; VL, viral load. † In such patients, if renal function subsequently improves (eGFR > 50 mL/min/1.73m2), then they can be switched to TDF + 3TC + DTG with creatinine monitoring.

    Key points about some of these alternative regimens can be found in Table 13

    TABLE 13: Alternative initial ART regimens for the previously untreated patient if DTG or TDF not tolerated
    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. 39
    • 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. 91, 92
    TDF + 3TC (OR FTC) + RPV
    • RPV cannot be used in patients receiving RIF.
    • RPV should not be used in initial therapy when baseline VL is > 100 000 copies/mL due to worse virologic outcomes.
    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 these patients.
    • 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 Southern Africa.
    3TC, lamivudine; ABC, abacavir; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; LTFU, loss to follow-up; RIF, rifampicin; RPV, rilpivirine; TDF, tenofovir; VL, viral load.
    Considerations for two-drug first-line regimen of dolutegravir + lamivudine

    Dolutegravir + lamivudine was shown to have noninferior efficacy to a three-drug regimen in RCTs. 93 However, these trials did not include patients with a VL > 500 000 copies/mL. 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, hepatitis B must be excluded before considering this regimen as patients with hepatitis B must receive TDF + 3TC (or FTC) to prevent rapid emergence of 3TC/FTC resistance.

    Common pitfall: Assuming all newly diagnosed patients are ART- naïve.

    In South Africa, many patients who present as newly diagnosed and report no prior treatment exposure have actually been on treatment before. Take a full, non-judgemental history from every “newly diagnosed” patient to ascertain if they may be returning to care after treatment interruption as this may impact management plans.