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

    Immune reconstitution inflammatory syndrome
            Key points
    • Approximately 10–20% of patients who start ART with advanced immunosuppression experience immune reconstitution inflammatory syndrome (IRIS) in the first few months of treatment.
    • Two forms of IRIS have been recognised, namely unmasking and paradoxical IRIS.
    • IRIS is most frequently described in association with tuberculosis (TB) and cryptococcal meningitis (CM).
    • InSTIs are not associated with an increased risk for TB-IRIS in clinical trials.
    • Early ART initiation (defined as 1–4 weeks after anti-tuberculous therapy) doubles the risk of TB-IRIS compared with late ART initiation (defined as 8–12 weeks after anti-tuberculous therapy), but ART should not be delayed for this reason.
    • There is no confirmatory diagnostic test for IRIS
    • In most instances, ART is continued in cases of IRIS, unless IRIS is life-threatening (e.g. neurological involvement in TB-IRIS with new focal findings or depressed level of consciousness).
    • Corticosteroids have been shown to reduce morbidity and improve symptoms in paradoxical TB-IRIS.

    Approximately 10–20% of patients who start ART with advanced immunosuppression experience clinical deterioration during the first few months due to IRIS. 126 Most presentations of IRIS occur within the first 3 months of ART. Two forms are recognised:

    • Unmasking IRIS occurs in patients who have an unrecognised opportunistic infection (OI) when ART is initiated, and who then present with exaggerated inflammatory features of that infection during early ART due to it being ‘unmasked’ by recovering immunity.
    • Paradoxical IRIS occurs in patients who are being treated for an OI when they start ART, but who develop an immune-mediated worsening or recurrence of features of that infection after starting ART.

    IRIS is most frequently described in association with TB and CM. Skin conditions such as molluscum contagiosum and Kaposi’s sarcoma may also worsen due to IRIS. The diagnosis of IRIS can be difficult, mainly because there is no confirmatory diagnostic test. Diagnosis relies on recognition of the characteristic clinical presentation, ensuring that OIs are correctly diagnosed, and excluding alternative causes for deterioration, such as drug resistance (e.g. multidrugresistant TB). Case definitions for TB and cryptococcal IRIS have been published. 127, 128 It is important to ensure that the underlying OI is treated appropriately. ART should be continued unless the IRIS is life-threatening (e.g. neurological involvement in TB-IRIS with depressed level of consciousness). Corticosteroids have been shown to reduce morbidity and improve symptoms in paradoxical TB-IRIS, 129 and can be used in mycobacterial and fungal forms of IRIS when other causes of deterioration have been excluded, and particularly when IRIS features are severe.

    For paradoxical TB-IRIS, prednisone can be commenced at a dose of 1.5 mg/kg/day and weaned over 4 weeks, but a longer course may be required if symptoms recur on weaning. 130 Steroids should not be used in patients with Kaposi’s sarcoma, as administration may be associated with worsening of disease and increased risk of mortality.

    Common pitfalls:
    • Using steroids in patients with Kaposi’s sarcoma, herpes infections and active hepatitis B.
    • Not counselling patients with advanced HIV disease about the potential for IRIS when initiating ART.
    Prophylactic prednisone
            Key points
    • Patients with active TB and who are improving on TB therapy with a CD4+ count ≤ 100 cells/µl, upon starting ART can be initiated on prednisone 40 mg daily for 14 days followed by 20 mg daily for 14 days to prevent paradoxical TB-IRIS.
    • The use of prednisone in this context is not associated with excess risk of severe infections, cancers or adverse events.

    The use of prophylactic prednisone for the prevention of paradoxical TB-associated IRIS in adults with a CD4+ count ≤ 100 cells/µl has been shown in a randomised trial to be associated with a 30% lower relative incidence of TB-IRIS. 131 Importantly, this did not cause an excess risk of severe infections or cancers. The recommended prednisone regimen is 40 mg daily for 14 days, followed by 20 mg daily for 14 days, and the prednisone should be started concurrently with ART. However, certain patient groups should be excluded from receiving prednisone, including patients with Kaposi’s sarcoma and patients with RIF-resistant TB, or whose TB has not improved prior to starting ART.

    Common pitfall: Using prophylactic prednisone in patients who are not improving on TB therapy.Common pitfalls: Refer these patients to an HIV-expert for a full assessment and management.