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

    Viral load

    Viral load (VL) monitoring is key to the success of ART. Decisions to change ART made on the basis of virological failure, rather than on clinical or immunological failure alone, have been shown to result in better patient outcomes.52 If the VL is undetectable, then the virus cannot mutate and develop resistance. A sustained VL < 50 copies/mL is associated with the most durable benefit. A suppressed VL also prevents transmission of HIV to contacts.

    Timing of viral load monitoring in the patient starting antiretroviral therapy

    FIGURE 1: Timing of viral load monitoring of the patient starting antiretroviral therapy. For patients with a viral load > 50 copies/mL on two consecutive occasions, refer to the text.
    (RPV, rilpivirine; VL, viral load)


    We recommend performing a baseline VL assessment for the following reasons:

    1. The 3-month VL can then be compared with the baseline VL to detect > 2 log10 drop, and if this has not occurred, then it allows for early adherence intervention.
    2. It may guide NNRTI selection (RPV should not be used if VL > 100 000 copies/mL).
    3. It confirms the diagnosis of HIV (antibody tests may very rarely give a false-positive result).

    A 3-month VL assessment is desirable to detect adherence problems early, before resistance develops. A subset of patients who start ART with a very high VL may not be fully suppressed at 3 months despite 100% adherence, but such patients would have had a > 2 log10 drop in VL from baseline if adherence is optimal and there is no resistance. Therefore, the 3-month result should be interpreted in relation to the baseline VL. All patients who have a detectable VL at 3 months should receive additional adherence interventions. In general, a patient’s VL declines fastest on InSTI-based regimens.

    If the 3-month VL is undetectable, then VL monitoring is recommended at 6 months and every 6 months thereafter. In patients who have an undetectable VL for > 12 months, and who demonstrate reliable adherence and follow-up, it may be acceptable to reduce the frequency of VL monitoring to 12-monthly.

    If the VL is > 50 copies/mL at any stage, then this should be an indication for urgent action. The patient should receive counselling and interventions should be implemented to improve adherence. A repeat measurement of VL should then be done in 2–3 months.

    Interpreting viral load results
    Virological criteria for treatment success

    Treatment success is defined as a decline in VL to < 50 copies/mL within 6 months of commencing ART, and sustained thereafter.

    Virological criteria for treatment failure
    Treatment failure is defined as a confirmed VL > 50 copies/mL on two consecutive measurements taken 2–3 months apart.

    The decision to alter ART should therefore be based on the results of repeat testing after 2–3 months, following intensive adherence counselling. Although previous guidelines used a threshold of 1000 copies/mL to define virological failure, there is now good evidence that a VL > 50 copies/mL is robustly associated with subsequent virological failure, although this has not been established.53,54 Sustained viral replication, even at these low levels, can lead to the accumulation of resistance mutations (although this has not yet been definitively established in the case of DTG).

    Viral blips

    Isolated detectable HIV VLs < 1000 copies/mL, followed by an undetectable VL, are termed ‘viral blips’ and alone are not a reason to change the ART regimen.

    • Viral blips can be caused by immune activation (such as from an acute infection), variability in the laboratory testing thresholds, or intermittent poor adherence. Provided that they are infrequent, and the VL returns to being undetectable at the next measurement, they are not regarded as consequential.
    Reasons for a high viral load

    A high VL can be attributed to one or more of these three factors:

    • inadequate patient adherence (most commonly)
    • resistance to the prescribed ART – including both acquired and transmitted drug resistance
    • inadequate ART drug levels as a result of altered pharmacokinetics, such as absorption difficulties, or drug-drug interactions.

    These explanations are not mutually exclusive. For instance, inadequate patient adherence frequently leads to the development of resistance in patients on a non-DTG-containing regimen.

    Transmitted drug resistance is currently increasing in the region.55 Such drug resistance is most frequently associated with the NNRTI class, since the signature K103N mutation has little effect on viral fitness and can therefore persist in the population even in the absence of drug pressure. Transmitted drug resistance to other drug classes is unusual; therefore first-line therapy with a DTG-based regimen is unlikely to be affected by this phenomenon.

    Interpreting a high viral load result in a patient receiving dolutegravir

    DTG has proven to be a remarkably robust drug in InSTI-naïve patients when paired with at least one active NRTI. To date, less than five cases of DTG resistance have been described in this scenario. Thus, while a high VL has traditionally been a marker of possible resistance, this paradigm no longer applies for the most part in patients receiving a DTG-based regimen, provided that:

    1. The patient has not had previous exposure to InSTIs as part of a failing regimen.
    2. The patient is known to have at least one fully active NRTI as part of their regimen. (Note that patients who contract HIV while on pre-exposure prophylaxis (PrEP) are at risk of not having a fully active NRTI backbone.)
    3. The patient was not recently exposed to a scenario where a drug-drug interaction would have substantially decreased DTG concentrations (e.g. RIF-based TB therapy without increasing DTG dosing frequency to 12-hourly).

    Provided that none of the above are met, a detectable VL should not be assumed to reflect possible resistance. Rather, it can be assumed that the detectable VL, if not fulfilling criteria for a viral blip, merely represents poor adherence, and efforts to address this should be undertaken. We do not recommend performing resistance testing for patients on a DTG-based regimen within 2 years of commencing the drug, provided the above conditions are met.