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








    Resistance and genotyping
            Key points
     
    • Adherence is the key to preventing drug resistance.
    • Resistance testing in patients failing DTG-based ART is unnecessary in the majority of cases, and should only be undertaken if specific criteria are met.
    • Resistance testing may not detect archived mutations to particular drugs if the patient is not receiving these drugs at the time of resistance testing.

    Overview

    As a result of transcription errors and recombination, HIV that is replicating can accumulate mutations that lead to drug resistance. Durable viral suppression by ART is required to limit the chances of developing drug resistance. Intermittent drug adherence, as opposed to a total lack of ART, provides a greater opportunity for resistance to develop, by exposing replicating virus to sub-therapeutic ART drug concentrations.

    ARV drug resistance mutations are summarised in Table 9.
     

    Tip: To best view this table, zoom in or rotate your mobile device into landscape orientation.

    TABLE 9: Antiretroviral drug resistance mutations.
    Drug Key mutations selected
    3TC or FTC Selects for M184V, which compromises both 3TC and FTC and slightly impairs the activity of ABC, but increases susceptibility to AZT and TDF.
    TDF Selects for K65R, which compromises TDF and ABC but increases susceptibility to AZT. TDF also selects for K70E, which causes low-level resistance to TDF, ABC, and possibly 3TC/FTC.
    ABC Selects for L74V, which compromises ABC. May also select for K65R, which compromises TDF and ABC but increases susceptibility to AZT. Selects for Y115F, which decreases its susceptibility.
    AZT Selects for TAMs, which may ultimately compromise all NRTIs.
    d4T Selects for TAMs, which may ultimately compromise all NRTIs.
    EFV or NVP Selects for K103N, which causes high-level resistance to EFV and NVP. Also selects for Y181C and other NNRTI mutations which cause resistance to EFV, NVP, RPV and ETR.
    RPV Selects for several mutations, including E138K, which compromise its susceptibility.
    PIs Multiple mutations usually required before seeing a decrease in susceptibility, especially for LPV and DRV, and cross-resistance between the PIs is common. ATV selects for I50L, which causes high-level resistance to ATV but not to the other PIs.
    RAL Selects for Q148H/K/R, Y143C and N155H, which cause resistance to RAL and, in certain combinations, to DTG too.
    DTG Very rarely selects resistance if InSTI-naïve, provided it is coupled to at least one other fully active drug. In patients with prior RAL exposure, mutations such as Q148H may cause decreased DTG susceptibility when combined with additional mutations.

    3TC, lamivudine; ABC, abacavir; ATV, atazanavir; AZT, zidovudine; d4T, stavudine; EFV, efavirenz; ETR, etravirine; DTG, dolutegravir; FTC, emtricitabine; InSTI, integrase strand transfer inhibitor; LPV, lopinavir; NVP, nevirapine; PIs, protease inhibitors; RAL, raltegravir; RPV, rilpivirine; TAMs, thymidine analogue mutations; NRTIs, nucleoside reverse transcriptase inhibitors; TDF, tenofovir disoproxil fumarate.


    When to perform a resistance test
    Baseline resistance test

    A baseline resistance test is not generally indicated. We recommend a baseline resistance test to guide first-line regimen choice only in the following situations:

    1. Pre-exposure prophylaxis (PrEP) received in the previous 6 months.
    2. History of sexual exposure to a person with known drug-resistant HIV or known to have failed an ART regimen.
    Resistance testing at treatment failure

    Resistance testing is generally only possible if the VL > 500 copies/mL. Patients with two or more consecutive VL results of 50–500 copies/mL are, however, still considered to have virological failure (see Module 8).

    Recommendations for resistance testing are summarised in Table 10.
     

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    TABLE 10: Recommendations for resistance testing.
    Regimen DTG-based therapy NNRTI-based therapy PI-based therapy
    First-line  Recommended if patient has been on regimen > 2 years  Not routinely recommended Not routinely recommended (rare scenario)
    Second-line Recommended if patient has been on regimen > 2 years  Recommended (rare scenario)  Recommended if patient has been on regimen > 2 years 

    First-line therapy
    Non-nucleoside reverse transcriptase inhibitor-based therapy

    A resistance test at failure of first-line therapy is not routinely recommended. The EARNEST and SELECT trials showed that without the use of a resistance test to decide which NRTIs to use in second-line therapy, virological outcomes were good and equivalent to a boosted PI + RAL regimen.60,61 However, where funds permit, resistance testing will offer some advantages:

    • A resistance test that shows no drug resistance may prevent having to switch unnecessarily to second-line therapy.
    • A resistance test may permit recycling of some first-line NRTIs (e.g. TDF), if they demonstrate susceptibility. This is particularly useful if one wants to carry through TDF (or ABC) to a second-line DTG-based regimen.
    • A resistance test will identify drug resistance that may be important to identify should the patient require third-line ART in future.
    Dolutegravir-based therapy

    Because resistance to DTG in first-line therapy is extremely uncommon, we do not recommend resistance testing unless the patient has been on a first-line DTG-based regimen for > 2 years, provided they were not 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).62 (Other rare indications for performing a resistance test before 2 years include patients who were infected with HIV while receiving pre-exposure prophylaxis (PrEP) – see Module 11.) 

    Because of the extreme rarity of first-line DTG-based resistance mutations, we suggest switching from a DTG-based first-line regimen to a second-line regimen only if resistance testing shows DTG resistance.

    Second-line therapy
    Non-dolutegravir-containing regimens
    • Resistance testing is recommended upon failure of second-line therapy. This enables clinicians to individualise a treatment regimen for third-line ART.
    • For PI-based regimens, sufficient resistance mutations to cause virological failure typically take at least 2 years to develop; therefore, in most cases, we recommend only performing a resistance test after the patient has been on a PI-based regimen for at least this duration. Exceptions include exposure to sub-therapeutic PI drug levels as a result of drug-drug interactions (e.g. not doubling the dose of LPV/r when using RIF-based TB treatment). Patients on PI-based therapy with a VL of 50–500 copies/mL pose a challenge as resistance testing is generally not possible. Such patients should remain on the same regimen with 2–3-monthly VL testing. If the VL rises > 500 copies/mL, then resistance testing should be performed, whereas if the VL re-suppresses to < 50 copies/mL, then the patient may revert to 6–12-monthly VL testing.
    Dolutegravir-based therapy

    We do not recommend performing resistance testing for DTG-based second-line therapies within 2 years where at least one active NRTI is present. For instance, if the patient’s first-line NRTIs were FTC and TDF, and the patient was switched to 3TC and AZT, then the strain of HIV can be assumed to be fully susceptible to AZT.

    Scenarios in which to consider resistance testing when failing on a DTG-containing regimen:

    • The patient previously developed resistance to other InSTIs (e.g. RAL).
    • The ART regimen may not contain any fully active NRTIs.
    • Accidental exposure to sub-therapeutic levels of DTG (e.g. RIF-based therapy was commenced without the DTG being given twice daily).
    Guide to interpreting a resistance test

    Current commercial tests have been licensed for specimens with a VL of at least 1000 RNA copies/mL. Nevertheless, many in-house assays can detect VLs between 500 and 1000 RNA copies/mL. In general, most commercial HIV resistance tests detect present mutations in > 10–20% of the HIV subpopulations in the sample.

    Common pitfall: Performing a resistance test in patients with a low or undetectable VL. Commercial assays may not be successful in samples where the VL < 500 – 1000 copies/mL.

    A key concept in interpreting resistance tests is archived resistance. After reverse transcription from its RNA template, HIV inserts a DNA copy of itself into the host genome. Some of the cells that HIV infects are extremely long-lived, and essentially provide an ‘archive’ of HIV variants over time. Thus, mutations that are known to have been present at one point in time can be assumed to be present for the lifetime of the patient, even if they are not visible on the patient’s latest resistance test.

    A second key concept is that of the wild-type virus, which is the naturally-occurring HIV strain free of drug-resistance mutations. In most cases, this form of the virus replicates more efficiently than viral strains that have acquired resistance. Therefore, when drug pressure is removed, the wild-type forms of the virus will predominate, even though the resistant strains have been archived and can become predominant again later if the drug pressure subsequently changes in ways favourable to these strains.

    • A prominent exception to this is the signature mutation of EFV and NVP, namely K103N, which imposes no significant fitness cost on the virus. Even after these drugs are stopped, the K103N strains may persist at detectable levels for several years.
    • Resistance testing should therefore only be performed when the patient is still taking their ART regimen, or up to a maximum of 4 weeks after discontinuation (see worked example in Box 1).
    • The absence of any identified resistance mutations implies that non-adherence is the cause of a raised VL.
    • This does not exclude the possibility of archived resistance, however, which may only become detectable once the patient is back on ART that suppresses the wild-type strain.
    • Any significant drug resistance mutations identified by resistance testing can be assumed to be present for the lifetime of the patient, even if subsequent resistance testing fails to show these mutations (as a result of worsened adherence or an ART switch, for instance).
    • Conversely, it is only possible to identify mutations reliably for drugs that the patient was currently taking when the resistance testing was performed, and for drugs affected by cross-resistance. ‘Susceptible’ results to drugs for which there is no drug pressure may be unreliable due to archived resistance.

    Common pitfall: Performing a resistance test in the absence of drug pressure. If the patient has defaulted therapy for more than a few weeks, then there is little purpose for a resistance test. In this scenario, it is highly likely that replication of wild-type virus will overtake and obscure any resistant strain, rendering them undetectable by commercial resistance testing.

    Tip: To best view this table, zoom in or rotate your mobile device into landscape orientation.

    BOX 1: Worked example of resistance testing.
    A patient was prescribed 3TC + TDF + EFV. When the patient failed this regimen after 1 year, the regimen was switched to 3TC + AZT + LPV/r. After 2 years, the patient failed this regimen too, therefore resistance testing was performed. The results showed the following:
    3TC/FTC: Resistant
    TDF: Susceptible
    ABC: Low-level resistance
    AZT: Resistant
    EFV: Resistant
    LPV/r: Low-level resistance
    Interpretation: 
    • Since the patient was receiving 3TC + AZT + LPV/r at the time of resistance testing, it is possible to interpret the results reliably for these drugs. All show at least a low level of resistance, thus the patient should be switched promptly to an alternative regimen.
    • EFV shows resistance, despite the patient not receiving the drug at the time of testing. This phenomenon is not uncommon with the K103N mutation.
    • TDF shows susceptibility. The patient was previously exposed to TDF, however. Although it is possible that none of the patient’s HIV strains have evolved TDF resistance, the patient was not receiving the drug at the time of resistance testing. Consequently, the possibility of archived resistance to TDF cannot be excluded.
    3TC, lamivudine; ABC, abacavir; AZT, zidovudine; EFV, efavirenz; HIV, human immunodeficiency virus; LPV/r, ritonavir-boosted lopinavir; TDF, tenofovir disoproxil fumarate.