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

    Management of patients currently receiving first-line therapy
            Key points
    • Clinicians can consider switching patients who are virologically suppressed on NNRTI-based first-line therapy from an NNRTI to DTG, while maintaining the same two-drug NRTI backbone.
    • In patients who are not virologically suppressed on an NNRTI-based regimen (VL > 50 copies/mL), we do not recommend an immediate switch to DTG, but rather enhanced adherence counselling with repeat VL measurement in 2–3 months. If the VL remains > 50 copies/mL, then these patients should be switched to a second-line DTG regimen which includes switching the NRTI backbone.
    • The typical criteriato define virological failure, of two VL measurements greater than a certain threshold despite an adherence intervention, are not appropriate for DTG-based regimens. Rather, in patients started on a first-line DTG regimen, we recommend switching to second-line therapy only if there is demonstrated InSTI resistance.

    Patients currently on an efavirenz-, rilpivirine- or nevirapine-based first-line regimen

    Such patients should have VL measurements performed 6–12-monthly (see Module 8 and Module 15). Given that DTG is now readily available, clinicians can consider switching patients who are known to have virological suppression (VL < 50 copies/mL within the last 6 months) from EFV (or NVP or RPV) to DTG while maintaining the same two-drug NRTI backbone. If the patient is tolerating the EFV (or RPV or NVP) regimen with no side-effects, then such a switch is optional, as the patient may develop DTG-related side-effects that they were not experiencing on the NNRTI (e.g. insomnia, weight gain). The benefit of such a switch is that a DTG regimen has a more robust resistance profile (DTG boasts a higher barrier to resistance than NNRTIs).12 An additional benefit of switching from NVP to DTG is that it is switching from a twice-daily to once-daily regimen. In patients experiencing EFV-related side-effects (even mild side-effects), we encourage a change to DTG while maintaining the same NRTIs, provided the VL is < 50 copies/mL within the last 6 months.

    Another option in patients who are virologically suppressed (VL < 50 copies/mL) while receiving a regimen of NNRTI + two NRTIs, and who have never experienced virological failure, is a switch to the two-drug combination of DTG + RPV. Data from two clinical trials (SWORD I and II)68 show that this regimen maintains virological suppression as a switch strategy in patients who have not previously experienced virological failure. This should not be done in patients who have chronic hepatitis B as TDF and 3TC (or FTC) should always form part of their treatment.

    The recommended protocol for switching from a first-line NNRTI-based regimen to a DTG-based regimen is outlined in Figure 3.

    FIGURE 3: Switching from a first-line non-nucleoside reverse transcriptase inhibitor-based regimen to a dolutegravir-based regimen.
    (DTG, dolutegravir; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor, VL, viral load)

    Antiretroviral therapy options in patients failing first-line non-nucleoside reverse transcriptase inhibitor-based therapy

    In patients who are not virologically suppressed on an NNRTI-based regimen (VL > 50 copies/mL), we do not suggest an immediate switch to DTG with the same two NRTIs. The reason is that it is possible that such patients have developed resistance to the two NRTIs and may then be placed on DTG without a fully effective drug to accompany it. In this scenario, we recommend enhanced adherence counselling and repeating the VL measurement in 2–3 months. If the VL is then < 50 copies/mL, then the patient can be switched to DTG + the same two NRTIs. If the VL remains > 50 copies/mL, then the patient should be switched to a second-line DTG regimen which includes DTG + two NRTIs as follows:

    • If the patient was receiving TDF (or ABC) + 3TC (or FTC) first-line therapy, then switch to AZT + 3TC in second-line therapy with DTG.
    • If the patient was receiving AZT (or d4T) + 3TC first-line therapy, then the decision regarding second-line therapy should be based on a resistance test result. If the virus is susceptible to TDF on resistance testing, then the clinician can prescribe TDF + 3TC (or FTC) + DTG (provided that the patient has not potentially previously experienced virological failure on TDF and has not previously experienced TDF nephrotoxicity). If no fully active NRTI is available to accompany DTG, then it is best to switch to PI-based second-line therapy with TDF + 3TC (or FTC). Advice is provided in Module 13 regarding patients who cannot access a resistance test in this scenario.

    WOCP should be counselled about the potential risk and benefits of DTG, and allowed to make an informed decision regarding the use of DTG and contraception (see Module 3).

    Patients started on a dolutegravir-based first-line regimen

    Such patients should have their VL measured 6–12-monthly (see Module 8 and Module 15). We have previously used the criteria of two VL measurements > 1000 copies/mL despite an adherence intervention to define virological failure and the need to switch from first- to second-line ART. This was appropriate for patients on NNRTI-based first-line regimens because of the low barrier to resistance of the NNRTI class. However, considerations are very different with DTG-based first-line regimens. In several clinical trials of DTG in first-line therapy, no DTG resistance has been described despite some patients having virological failure; and in clinical practice very few cases of DTG resistance (< 5 cases worldwide at the time of writing) have been described when the drug has been used as part of a three-drug first-line regimen.63 Therefore, it would be inappropriate to use the same criteria for switching to second-line ART for DTG as it is likely that most patients with two unsuppressed VLs will not have resistance and rather require improved adherence on the same first-line regimen to achieve suppression. For that reason, we only recommend switching from first-line DTG-based ART to second-line if resistance testing demonstrates InSTI resistance.

    Until further data are available, in patients with an unsuppressed VL on DTG-based first-line ART, we recommend enhanced adherence counselling. The tolerance of the regimen should also be addressed – the regimen may need to be switched due to side-effects. InSTI-resistance testing should be considered in these situations:

    • DTG monotherapy for a period (DTG resistance has been more frequently described in this situation).63
    • Co-administration of a drug that interacts with DTG without necessary dose adjustment (e.g. DTG given at 50 mg daily with RIF or given simultaneously with polyvalent cation-containing agents – see Module 3).
    • VL measurements > 50 copies/mL for > 2 years (despite adherence interventions, 100% pharmacy refills and self-reported adherence) and the current VL is > 500 copies/mL thereby permitting a resistance test.
    • The patient was infected while receiving PrEP (because of potential NRTI resistance at the time of infection).
    • Sentinel surveillance projects or research studies – with the purpose of detecting emergence of DTG resistance.

    If a resistance test is performed, then this should include sequencing of the integrase enzyme. The clinician should only switch from a DTG-based first-line regimen to second-line therapy if resistance is detected, and the drugs used in the second-line regimen should depend on the resistance test result (see Module 13).

    These recommendations are based on accumulated information on the resistance barrier to DTG to date suggesting that DTG resistance is extremely rare when the drug is used in a three-drug first-line regimen. These recommendations may be updated when more data become available regarding incidence and risk factors for DTG resistance with more widespread use in routine clinical practice.

    Figure 4 outlines the virological monitoring of patients on DTG-based first-line ART and the recommended response to results.

    FIGURE 4: Virological monitoring of patients receiving dolutegravir-based first-line antiretroviral therapy and response to results.
    (DTG, dolutegravir; NRTIs, nucleoside reverse transcriptase inhibitors; VL, viral load)