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

    Integrase strand transfer inhibitor class of antiretroviral drugs

    Overview of integrase strand transfer inhibitors

    Integrase strand transfer inhibitors (InSTIs) – often simply termed ‘integrase inhibitors’ – work by preventing the transfer of proviral DNA strands into the host chromosomal DNA. Currently, two InSTIs are available in southern Africa: dolutegravir (DTG) and raltegravir (RAL). DTG is preferred to RAL due to its higher barrier to resistance, its availability in FDC formulation, and the ability to take the drug once daily. The SPRING-2 trial compared DTG- and RAL-containing first-line regimens and found no significant differences in virological suppression, and adverse effects were similar between treatment groups;11 however, although no patients in the DTG arm were found to have developed resistance, one patient in the RAL arm developed InSTI resistance and four developed NRTI resistance. The high barrier to resistance of DTG-containing ART regimens has been replicated in other first-line studies and in a study of ART-experienced patients in which DTG was compared to RAL.12-14 In a meta-analysis that included clinical trials and observational studies, the emergence of InSTI resistance was more common with RAL than with DTG (3.9% vs. 0.1%).15 However, the emergence of InSTI resistance in patients receiving RAL can compromise second-generation InSTIs such as DTG.

    DTG use has been shown to be superior to EFV-based ART in the SINGLE trial.12 This difference was largely driven by the superior tolerability of the DTG arm: 2% vs. 10% in the EFV arm had an adverse event leading to discontinuation of the study drug. DTG showed superior rates of viral suppression (71% vs. 63% respectively at 144 weeks).

    DTG-based regimens have also been shown to be superior to PI-based regimens. As first-line therapy, DTG was superior to DRV/r with respect to both viral suppression rates and side-effect profile.13 The ARIA trial of ART-naïve women demonstrated DTG’s non-inferiority to ATV/r, although with a statistically significantly higher rate of viral suppression and fewer side-effects overall.16 In the DAWNING trial considering second-line regimens, DTG was superior to LPV/r.17 Importantly, at least one fully active NRTI was genotypically confirmed at baseline in this trial.

    Data from the Tsepamo surveillance study in Botswana demonstrated a statistically higher rate of neural-tube defects (NTDs) among women who were taking DTG at the time of conception (0.3% vs. 0.1% in women receiving other ART in the periconception period).18 Unlike in South Africa, folate fortification of staple foods does not occur in Botswana. In contrast to the Botswana data, no NTDs were reported in a Brazilian cohort of 1468 women, 382 of whom were DTG-exposed.19 Although additional data will undoubtedly be forthcoming, it should be noted that the absolute risk is < 0.5%, and this risk may be outweighed by the additional benefits of DTG over alternative therapies. We recommend that women of childbearing potential (WOCP), particularly those who wish to become pregnant or who have no reliable access to effective contraception should be counselled adequately about the potential risks and benefits of DTG- vs. EFV-based ART, and should be offered a choice of first-line regimens.

    Common side-effects

    DTG and RAL are generally well tolerated, with most side-effects being mild and very rarely leading to discontinuation. DTG may cause a mild increase in sCr due to interference with tubular secretion. This does not represent renal damage and is not an indication for switching to another drug. The rise in sCr occurs within the first few weeks, and persists for as long as the patient remains on DTG.

    Common pitfall: Assuming that the rise in sCr seen in patients on DTG necessarily represents renal failure. In reality, the effect of DTG on creatinine secretion is of no consequence and does not represent a decline in renal function.

    RAL and DTG can cause headaches when started, but this usually resolves. These drugs may also cause insomnia and neuropsychiatric side-effects. RAL and DTG can occasionally cause hypersensitivity rashes, including life-threatening rashes. Weight gain is more pronounced in patients taking an InSTI as part of their ART regimen (with the exception of cabotegravir, which is not currently available in South Africa). Black women, patients with low baseline CD4+ counts, and patients with high baseline VLs appear to be at greatest risk.20 The risk also appears to be moderated by the companion drugs in the patient’s ART regimen. In the ADVANCE trial, women on a tenofovir alafenamide (TAF) + FTC + DTG regimen gained a median of 10 kg over 96 weeks, with little evidence of a plateau in the increase.21 In women, median weight gain in the same period in the TDF + FTC + DTG arm was 5 kg, and 3 kg in the TDF + FTC + EFV arm. In men, weight gain was approximately half as much in each arm. The long-term health implications of these findings are currently unclear, but clinicians should be aware of the possibility of weight gain, and encourage appropriate exercise and dietary measures to limit this.

    Dosage and common adverse drug reactions of InSTIs are described in Table 3.

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    TABLE 3: Dosage and common adverse drug reactions of integrase strand transfer inhibitors available in southern Africa.
    Drug Recommended dosage Common or severe ADR
    RAL 400 mg 12-hourly Headache and other CNS side-effects, GI upset, hepatitis and rash (rare), rhabdomyolysis (rare). Weight gain.
    DTG 50 mg daily Insomnia, headache and other CNS side-effects, GI upset, hepatitis and rash (rare). Possibly teratogenic. Weight gain.

    ADR, adverse drug reaction; CNS, central nervous system; DTG, dolutegravir; ETR, etravirine; GI, gastrointestinal; PI, protease inhibitor; RAL, raltegravir.

    Key drug-drug interactions with dolutegravir

    Key drug-drug interactions involving DTG are summarised in Table 4.

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    TABLE 4: Key drug-drug interactions with dolutegravir.
    Drug Action required
    RIF Administer DTG twice-daily (i.e. 50 mg 12-hourly) until 2 weeks after stopping RIF.
    Metformin Do not exceed metformin 500 mg 12-hourly.
    Carbamazepine, phenytoin Give alternative anticonvulsant if possible (e.g. lamotrigine or topiramate).

    If carbamazepine is used, then administer DTG 12-hourly.

    Avoid phenytoin with DTG altogether.
    Polyvalent cation-containing agents (e.g. antacids, laxatives, sucralfate, iron and calcium supplements) For magnesium-/aluminium-containing antacids, administer > 2 hours after or > 6 hours before DTG dose.

    For iron/calcium supplements, either take with food or apply intervals above.
    Etravirine Do not use DTG + etravirine together unless a boosted PI is also used in the combination.

    DTG, dolutegravir; RIF, rifampicin, PI, protease inhibitor.

    Common pitfall: Forgetting to dose DTG twice daily when rifampicin (RIF)-based tuberculosis (TB) treatment is commenced.