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
    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

    CD4+ cell count
            Key points
    • All HIV-positive patients should be started on ART irrespective of their CD4+ counts.
    • CD4+ counts should be used only to establish whether CTX prophylaxis and sCrAg testing is required (CD4+ count < 200 cells/μL).
    • Monitoring ART efficacy is best established using VL, not CD4+ count.
    • Most patients newly initiating ART with an abnormally low CD4+ count will see a rapid initial CD4+ count increase (75–100 cells/μL), followed by a more gradual rise thereafter (50–100 cells/μL per year) until a normal CD4+ count > 500 cells/μL is achieved.
    • If CD4+ count does not rise despite viral suppression, then the ART regimen does need to be altered. This phenomenon may reflect an ‘immunological discordant response to ART’; although if the patient is unwell, then other secondary causes should be sought.

    Role of CD4+ count monitoring

    A CD4+ count < 200 cells/μL indicates the need for CTX prophylaxis, principally to prevent Pneumocystis jirovecii pneumonia, although CTX is also active against other opportunistic pathogens, including Toxoplasma gondii, Cystoisospora belli and Nocardia spp. A baseline CD4+ count < 200 cells/μL is also an indication to reflexly perform sCrAg testing. If the CD4+ count > 200 cells/μL at baseline or it increases above this threshold on ART, then CD4+ testing can be stopped, since therapeutic monitoring on ART is best accomplished with VL, not CD4+ count or clinical criteria. However, if virological or clinical failure occurs, then the CD4+ count should be repeated, as CTX prophylaxis should be commenced if the count drops to < 200 cells/μL on ART.

    Common pitfall: Routinely assessing CD4+ counts if the previous result was > 200 cells/μL. This is unnecessary unless virological or clinical failure subsequently occurs.

    Timing of CD4+ count measurements

    CD4+ counts should be performed:

    • At baseline (to guide decisions about CTX prophylaxis)
    • Every 6 months thereafter if the previous CD4+ count was < 200 cells/μL.
    CD4+ count response

    In patients who start ART with an abnormally low CD4+ count, the CD4+ count typically increases rapidly in the first month of ART, by ~75–100 cells/μL, with a more gradual rise thereafter (50–100 cells/μL per year).56 Most patients achieve a CD4+ count > 500 cells/μL after several years of ART, provided that the VL remains suppressed. However, CD4+ count responses are highly variable and may fail to increase despite virological suppression in about 10–20% of patients.57,58 Such patients have a delayed or absent CD4+ count response to ART despite viral suppression, which is termed an ‘immunological discordant response to ART’, previously, ‘immune non-responders’. Certain studies suggest that older patients are at higher risk of this response. There is no evidence that such patients benefit from a change in ART regimen; therefore, the same regimen should be continued. CTX prophylaxis should be continued if the CD4+ count remains < 200 cells/μL. There is evidence that the prognosis of such patients is worse than in those who have a CD4+ response, but better than that of patients experiencing both virological and immunological failure.58 If patients with an immunological discordant response to ART are clinically unwell, then TB or lymphoma should be considered as the cause of persistent CD4+ lymphopenia. CD4+ counts may remain stable in the presence of incomplete viral suppression in patients receiving ART until the VL is high (approximately ≥ 10 000 copies/mL).59

    Common pitfall: Confusing an ‘immunological discordant response to ART’ with treatment failure. There is no role for switching ART if the VL is suppressed.

    Figure 2 outlines the suggested approach to patients with low CD4+ counts despite a suppressed VL on ART.

    FIGURE 2: Suggested approach to patients with low CD4+ counts despite a suppressed viral load on antiretroviral therapy.
    (ART, antiretroviral therapy; CD4+, cluster of differentiation 4; OIs, opportunistic infections; SLE, systemic lupus erythematosus; TB, tuberculosis; VL, viral load)